Patent Review
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Metabotropic glutamate receptor 5-negative allosteric modulators for the treatment of psychiatric and neurological disorders (2009–July 2013) Guiying Li*1, Morten Jørgensen2 & Brian M Campbell3 Negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu5) have been actively pursued for over a decade as a potential treatment for anxiety, depression, substance abuse, pain, levodopa-induced dyskinesia in Parkinson’s disease, fragile X Syndrome, autism, gastroesophageal reflux disease and lower-urinary-tract disorders. This article begins with an introduction of preclinical validation of potential therapies for psychiatric and neurological disorders, and of clinical results, followed by a comprehensive overview of the mGlu5-negative allosteric modulator patent applications published between 2009 and July 2013, with a focus on the analysis of structure and in silico CNS drug-like properties of example compounds and disclosed data. Given positive results in proof-ofconcept studies in humans for certain indications such as levodopa-induced dyskinesia in Parkinson’s disease, fragile X Syndrome, gastroesophageal reflux disease, migraine and anxiety, and the soaring chemical diversity among the mGlu5-negative allosteric modulators, there is reason to believe that a drug will emerge from this therapeutic class in the near future.
Glutamate is the primary excitatory neurotransmitter in the CNS acting on both ionotropic and metabotropic glutamate (mGlu) receptors. mGlu receptors belong to the class C of G-protein-coupled receptor superfamily and are divided into three groups and eight subtypes based on homology, pharmacology and signal transduction mechanisms: group I (mGlu1,5), group II (mGlu 2,3) and group III (mGlu4,6,7,8) [1]. mGlu5 is located primarily on neuronal postsynaptic excitatory terminals and glia, coupled to Gq/11 protein and activate phospholipase C resulting in increased intracellular calcium release [2]. mGlu5 is highly expressed in the CNS and is concentrated in the cortex, hippocampus, and basal ganglia, regions important in many neurological and psychiatric disorders [3,4]. This receptor has important functions in regulating neuronal development and synaptic maintenance, which has led to the prediction of its involvement in a variety of CNS-related disorders [5–7]. Selective orthosteric ligands for mGlu receptors have been challenging to find, although a few exist [8,9]. Because of this, much of the work done to delineate the role of mGlu5 in CNS physiology has focused on allosteric modulators. A wealth of preclinical data supporting the therapeutic potential of mGlu5-negative allosteric modulators (NAMs) for treating CNS disorders were summarized in recent reviews [5,6], including beneficial effects of extensively used tools 2-methyl6-(phenylethynyl)pyridine (MPEP) (Figure 1; 1), 3-([2-methyl-4-thiazolyl]ethynyl)pyridine (Figure 1, 2) and fenobam (Figure 1; 3) in animal models of fragile X syndrome (FXS) (e.g., fragile X mental retardation 1 [Fmr1]-mutant mice), Parkinson’s disease (PD) and levodopa (l-DOPA)-induced dyskinesia in PD (PD-LID)
10.4155/PPA.13.58 © 2013 Future Science Ltd
Pharm. Pat. Analyst (2013) 2(6), 767–802
Discovery Chemistry & DMPK, Lundbeck Research USA, 215 College Rd., Paramus, NJ 07661, USA 2 Discovery Chemistry & DMPK, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark 3 Neuroinflammation, Lundbeck Research USA, 215 College Rd., Paramus, NJ 07661, USA *Author for correspondence: Tel.: +1 201 350 0140 Fax: +1 201 261 0623 E-mail: [email protected] 1
ISSN 2046-8954
767
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Li, Jørgensen & Campbell
(reversal of motor impairments in rodents or primates treated with Orthosteric ligands: Compounds 6-hydroxydopamine (6-OHDA) or that bind to the same site as the 1-methyl-4-phenyl-1,2,3,6-tetrareceptor’s endogenous ligand hydropyridine), anxiety (e.g., fear (e.g., glutamate). potentiated startle, contextual fear Allosteric modulators: Ligands conditioning, Vogel conflict drinkthat bind to a site that is ing, Geller Seifter [GS] test, stresstopographically distinct from the orthosteric binding site. induced hyperthermia [SIH], elevated plus maze, defensive marble Negative allosteric modulators: burying [MB]), substance abuse Ligands that bind to an allosteric sites and inhibit the action of the (e.g., drug self-administration and orthosteric agonists (e.g., conditioned-place preference) and glutamate). The negative chronic pain (e.g., allodynia modmodulator attenuates the effects els). Preclinical studies of newer seof the orthosteric ligand without lective compounds with improved triggering a functional activity on drug-like properties such as MRZits own in the absence of the 8676 (Figure 1; 4), 2-chloro-4-([2,5orthosteric ligand. dimethyl-1-(4-[trif luoromethoxy] Golden Triangle: Triangular phenyl)-1H-imidazol-4-yl]ethyshaped area defined by plotting nyl)pyridine (CTEP) (Figure 1; molecular weight (MW) versus 5), and GRN-529 (Figure 1; 6), cLogD7.4 with a base-line from as well as front-running agents LogD = -2.0 to LogD = 5.0 at in the clinic such as mavoglurant MW = 200 and an apex at LogD = 1.5 and MW = 450. (Figure 1; AFQ056, 7), and dipraglu Compounds inside this area tend rant (Figure 1; ADX48621, 8), were to have a higher probability of published recently. Mavoglurant, success in achieving good dipraglurant, and MRZ-8676 were metabolic stability and shown to alleviate dyskinetic-like membrane permeability than behaviors in animals where dopathose outside of the area based mine neurons had been ablated on an analysis by Pfizer scientists. with neurotoxic agents such as Multiparameter optimization 6-OHDA or 1-methyl-4-phenylscore: Desirability function based 1,2,3,6-tetrahydropyridine [10–12]. on six in silico physicochemical In Fmr1 knockout mice, a model of parameters (molecular weight, FXS, mavoglurant rescued deficits ALogP, cLogD7.4, topological polar surface area, number of H bond in prepulse inhibition and social donors and pKa). This score ranges behaviors [13,14]. In the same model, from 0 (lowest) to 6 (highest). A CTEP showed comprehensive phescore ≥4 is indicative of good CNS notype correction including reverdrug-like properties. sal of elevated hippocampal longterm depression, protein synthesis, and audiogenic seizures after acute treatment. CTEP also rescued cognitive deficits, auditory hypersensitivity, aberrant dendritic spine density, overactive ERK and mTOR signaling, and partially corrected macroorchidism following chronic administration [15]. In addition, this compound demonstrated anxiolytic-like activity in SIH in mice and Vogel conflict drinking in rats [16]. In mouse models of autism, GRN-529 alleviated multiple behavior symptoms of autism including repetitive behaviors, spontaneous stereotyped jumping and lack of sociability [17]. Although more limited in scope, mGlu5 NAMs also show antidepressant efficacy Key terms
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in tail suspension assay and forced swim test as was recently shown with GRN-529 [18]. With the plethora of preclinical data supporting the potential efficacy of mGlu5 NAMs in human disease and evidence of mGlu5 signaling dysregulation in a range of CNS pathologies [5], it is no surprise that significant efforts have been made to develop drug-like molecules for testing the clinical efficacy of this target. In recent years, at least nine mGlu5 NAMs have entered into clinical studies [19], of which at least four (mavoglurant, dipraglurant, RO4917523 [RG7090] [Figure 1; 9] and fenobam) continue to be actively pursued. Proof-of-concept in patients was achieved for several indications including PD-LID with mavoglurant [20] and dipraglurant [201], gastroesophageal reflux disease (GERD) and migraine with raseglurant (Figure 1; 10) [21,22], and anxiety with fenobam [23]. Results in FXS have been less straight forward. Mavoglurant was not effective in treating symptoms in a broad cohort of FXS patients [24], however, in a secondary analysis, patients with full methylation of the Fmr1 gene promoter showed significant improvement, supporting efficacy by mGlu5 NAMs in a subpopulation of this indication as well. Fenobam was also evaluated in an open label trial in FXS patients where it reduced prepulse inhibition in these patients indicating the potential for a beneficial effect on sensory gaiting [25]. With substantial preclinical support, as well as encouraging proof-of-concept clinical data, a great deal of effort has gone into discovering new mGlu5 NAM drug candidates in recent years. Companies have also tried to improve the developability and drug efficacy via formulation or prodrug approaches. This article provides a comprehensive overview of patent applications published between 2009 and July 2013 and focuses on the analysis of structure, in silico CNS drug-like properties such as the Golden Triangle [26] and multiparameter optimization (MPO) score [27], and disclosed data of supporting compounds. Patent analysis (publications during 2009 & July 2013)
Approximately 190 mGlu5 NAM patent applications have been published since 2000. The scope of this article is to analyze the structures, drug-like properties and biological data of mGlu5 NAMs in 66 patent applications that appeared between 2009 and July 2013. The drug-like property analysis was based on a number of molecular descriptors as follows: molecular weight (MW); ALogP (calculated value for the lipophilicity of a molecule expressed as log [octanol/water partition coefficient]); cLogD 7.4 (calculated value for the lipophilicity of a molecule expressed as log [octanol/aqueous buffer at pH 7.4 distribution coefficient]); topological
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mGlu5-negative allosteric modulators for the treatment of psychiatric & neurological disorders
polar surface area; number of H bond donors; and basic pK a (basicity of the most basic center). These parameters were calculated using Pipeline Pilot components (v8.5) and then used for the MPO and Golden Triangle analyses. The average MW, ALogP and MPO scores ± SD, and percentage of the compounds inside the Golden Triangle of the example compounds from each application are listed in the summary Tables 1–9. The mGlu5 NAMs outside the scope of this article, either in patent applications or in the primary literature, have been previously discussed in several reviews [9,28–30].
N
N
S
N
N O 2 MTEP
1 MPEP
O
Cl
O
3 Fenobam, Phase I/II N
N
H N
N NH
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OCF3 N
Cl
N 5 CTEP
4 MRZ-8676 O
N
N
O
O
H
N
■■ Novartis AG
H OH
Novartis published nine patent apOCHF2 7 Mavoglurant (AFQ056) plications during 2009–2012 with 6 Phase II/III focus on utility and improvement GRN-529 in drug properties and/or developN ability of their previously patented N F lead series especially the mavoglurant chemotype. The patent numN Cl N ber, compound information, title, N CNS drug-likeness and disclosed N F 9 data are summarized in Table 1. RO4917523 (RG7090) 8 Phase II There are three patent applicaDipraglurant (ADX48621) tions covering the use of the comPhase II pounds within Markush structures NH2 in previous applications [101–103]. F The first application claiming the N use of mGlu5 modulators for the 10 treatment, prevention or delay of Raseglurant (ADX10059) progression of PD appeared in discontinued 2009 [104]. An unspecific compound A was reported to potentiFigure 1. Metabotropic glutamate receptor 5-negative allosteric modulators in vivo tools and ate the antiparkinsonian response example clinical compounds. of low dose l-DOPA at 25 mg/kg, CTEP: 2-chloro-4-([2,5-dimethyl-1-(4-[trifluoromethoxy]phenyl)-1H-imidazol-4-yl]ethynyl)pyridine; peroral (p.o.) after either acute or MPEP: 2-methyl-6-(phenylethynyl)pyridine; MTEP: 3-([2-methyl-4-thiazolyl]ethynyl)pyridine. repeated administration. The second application claiming the use of an mGlu5 modulator for the treatment, prevention the company’s development compound mavoglurant, or delay of progression of a pervasive developmental was disclosed to have antidyskinetic effect in combinadisorder such as FXS and fragile X-associated tremor/ tion with l-DOPA in human patients and in parkinsoataxia syndrome was also published in 2009 [105]. The nian monkeys. Detailed studies have been reported in third application claiming the use of an mGlu modu- primary papers [10,20]. None of the three applications lator in combination with at least one of l-DOPA, a claimed any specific compounds. A fourth use patDOPA decarboxylase inhibitor, a catechol-O-methyl ent application claiming combinations of a7 nicotinic transferase inhibitor or a dopamine agonist was pub- acetylcholine receptor activators and mGlu5 antagolished in 2010 [106]. An unspecific compound A, likely nists for treating PD-LID was published in 2012 [107].
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770
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4-tolyl-ethynyl-octahydo-indole-1-ester derivatives
WO2012101058A1 Prodrug Markush structure 12; 95 supporting compounds
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Ltk-cells expressing hmGlu5 were used in in vitro mGlu5 functional assays.
Combinations of a7 nicotinic acetylcholine NA receptor activators and mGluR5 antagonists for use in dopamine induced dyskinesia in Parkinson’s disease
441 ± 39 4.6 ± 1.5
NA
3.7 ± 0.7
5.3 ± 0.5
5.1
5.1
NA
3.5 ± 0.3
NA
NA
NA
0
89
100
100
NA
0
NA
NA
[107]
[111]
In vitro human/rat liver microsomal CLint and solubility of selected compounds; plasma and brain exposure of two prodrugs and mavoglurant
In vitro a7-nAChR activity of three selected compounds; effect of MPEP, JN403 and combination of these two compounds in parkinsonian primates
[110]
[108]
FMRP mRNA transcript, FMRP protein level, or Fmr1 gene methylation IC50 values of 9 compounds at hmGlu5 (16–1430 nM) and solubility at pH 6.8 of these compounds specified. No in vivo data
[109]
[106]
[112]
[105]
[104]
Ref.
No biological data
Antidyskinetic effect of an unspecified compound in combination with l-DOPA in human patients and parkinsonian primates
Percentage inhibition of inositol phosphonate turnover at 0.1 µM. No in vivo data
No specific data
Antidyskinetic effect of an unspecified compound in parkinsonian primates
MPO ± SD % in Disclosed data† Golden Triangle
glutamate receptor 5; l-DOPA: Levodopa; MPEP: 2-methyl-6-(phenylethynyl)pyridine; MPO: Multiparameter optimization; MW: Molecular weight; NA: Not analyzed.
ALogP: Calculated value for the lipophilicity of a molecule expressed as log (octanol/water partition coefficient); CLint: Intrinsic clearance; FMRP: Fragile-X mental retardation protien; hmGlu5: Human metabotropic
†
WO2012127393A1 Use patent
4-(hetero)aryl-ethynyl-octahydro-indole1-carboxylic acid esters
WO2012084873A1 Markush structure 11; 9 supporting compounds
321 ± 9 2.6 ± 0.6
Predictive markers useful in the treatment 313 of fragile X syndrome. 3.3
WO2011137206A1 Mavoglurant
313 3.3
NA
403 ± 29 5.9 ± 0.8
Processes for the preparation of 4-oxooctahydro-indole-1-carboxylic acid methyl ester and derivatives thereof
Combination products
Organic compounds
NA
NA
MW ± SD ALogP ± SD
WO2010018154A1 Mavoglurant
[101–103]
WO2010000763A2 Use patent covering compounds in
US20090105266 Markush structure 13; 127 supporting compounds
[101–103]
WO2009047303A2 Use patent covering compounds in
Organic compounds
Organic compounds
WO2009047296A2 Use patent covering compounds in
[101–103]
Original title
Patent number and compound information
Table 1. Summary of Novartis patent applications.
Patent Review Li, Jørgensen & Campbell
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mGluR5: Metabotropic glutamate receptor 5; MPO: Multiparameter optimization; MW: Molecular weight.
Epstein-Barr nuclear antigen cell membranes expressing hmGlu5 were used in a [3H]-2-methyl-6-(phenylethynyl)pyridine binding assay.
ALogP: Calculated value for the lipophilicity of a molecule expressed as log (octanol/water partition coefficient); GERD: Gastroesophageal reflux disease; hmGlu5: Human metabotropic glutamate receptor 5;
†
[117]
In vitro dissolution profile of various compositions of RO4917523 in simulated gastric fluid and simulated intestinal fluid. PK of RO4917523 in cynomolgus monkeys following different immediate and modified release formulation Pharmaceutical compositions of mGluR5 antagonists WO2012019990A2 Markush structure 14; 45 supporting compounds
367 ± 32 5.0 ± 0.9
3.3 ± 0.8
2
[116]
In vitro dissolution profile of various compositions of RO4917523 in simulated gastric fluid and simulated intestinal fluid. PK of RO4917523 in cynomolgus monkeys following different immediate and modified release formulation Pharmaceutical compositions of mGluR5 antagonists WO2012019989A2 Markush structure 14; 45 supporting compounds
367 ± 32 5.0 ± 0.9
3.3 ± 0.8
2
[115]
Ki values of 57 compounds at hmGlu5 specified (33–817 nM). No in vivo data 81 5.6 ± 0.3 Imidazole derivatives as mGluR5 antagonists WO2011006910A1 Markush structure 15; 57 supporting compounds
337 ± 24 2.4 ± 0.5
[118]
Ki values of 40 compounds at hmGlu5 (5–109 nM). No in vivo data 98 5.5 ± 0.4 Pyridine-2-ylcarboxylic acid amides WO2010100050A1 Markush structure 16; 53 supporting compounds
274 ± 21 2.4 ± 0.7
[114]
Ki values of 28 compounds at hmGlu5 (5–211 nM) specified. No in vivo data 2 3.3 ± 0.8 Use of mGluR5 antagonists for the treatment of GERD WO2009024491A1 Markush structure 14; 43 supporting compounds
361 ± 54 5.0 ± 1.2
Disclosed data† MPO ± SD % in Golden Triangle Original title
MW ± SD ALogP ± SD
Patent Review
Patent number and compound information
Table 2. Summary of Roche patent applications
These claims were supported by improved antiparkinsonian scores when using the combination of MPEP and nAChR a7-selective agonist JN403 ([S]-[1-azabicyclo(2.2.2)oct-3-yl]-carbamic acid [S]-1-[2-fluoro-phenyl]-ethyl ester) relative to each compound alone in Parkinsonian primates. Two mGlu5 NAMs, MPEP and 2-([1S,2S]-2-carboxycyclopropyl)-3-(9Hxanthen-9-yl)-d-alanine (LY341495) were specifically claimed [31]. A patent application concerning predictive markers useful in the treatment of FXS was published in 2011 in which mavoglurant was specifically claimed as a treatment agent [108]. The invention was based on the finding that the methylation status of the Fmr1 gene region and/or a reduction in the level of Fmr1 gene expression along with FMRP, the translational product of the gene, can be used to predict responsiveness to mGlu5 treatment in patients with FXS. Results of the clinical trial along with the secondary data analysis were published [24]. Further patent estate related to mavoglurant includes an invention related to the processes for the preparation of mavoglurant and derivatives, which was published in 2010 [109]. It claimed production and use of mavoglurant, intermediates and salt forms. Efforts to improve developability of mavoglurant series were described in two patent applications published in 2012. The first application related to a series of 4-(hetero)aryl-ethynyl-octahydro-indole-1-carboxylic acid esters with improved solubility [110]. The application specifically mentioned that there is a need for mGlu5 antagonists that are good drug candidates possessing the following attributes: low binding to plasma proteins, good absorption from the GI tract, sufficient metabolic stability, favorable PK profile for a long-lasting blood exposure after oral administration while avoiding an overly high maximum plasma concentration (Cmax), nonhygroscopicity, easy formulation, lack of toxicity and fewer side effects. Furthermore, good solubility in water was specifically highlighted for drugs intended for pediatric uses (e.g., with infant FXS patients). Of the nine exemplified compounds of formula 11 (Figure 2), seven have X as OH; and two have X as NH2; eight have R1 as Me, and one has R1 as Et. Ring A is 3-chlorophenyl, m-tolyl (in two compounds), 5-methylpyridin-3-yl, 2-methylpyridin-4-yl, 6-methylpyridin-2-yl, 2-chloropyridin-4-yl, 4-methylpyridin-2-yl or 2-methylthiazol-4-yl. All nine compounds were evaluated for efficacy in a calcium mobilization functional assay against human mGlu5 (hmGlu5), which was expressed in Ltk-cells. The solubility of eight compounds in chloride-free phosphate buffer (pH 6.8) was determined. Representative compound 11a (Figure 2) was the most potent with decent
Ref.
mGlu5-negative allosteric modulators for the treatment of psychiatric & neurological disorders
771
772
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Pyrazolopyrimidines, 285 ± 46 a process for their 3.2 ± 1.1 preparation and their use as medicine Crystalline forms of substituted pyrazolopyrimidines mGluR modulators
mGluR modulators
mGluR modulators
Enteric formulations of mGluR modulators mGluR modulators
WO2010063487A1 Markush structure 22; 188 supporting compounds
WO2011064237A1 Compound 17a
WO2012052451A1 Markush structure 23; 131 supporting compounds
WO2012085166A1 Markush structure 20; 48 supporting compounds
WO2012085167A1 Markush structure 21; 95 supporting compounds
WO2012139876A1 Markush structure 17; 242 supporting compounds
WO2012152854A1 Markush structure 24; 40 supporting compounds
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4.1 ± 0.8
5.4 ± 0.5
5.0 ± 0.6
5.1 ± 0.5
5.0 ± 0.7
4.9 ± 0.5
5.4
50
80
15
45
83
63
0
76
54
15
[122]
No in vitro and in vivo biological data
FLIPR EC50 or IC50 values of all exemplified compounds at hmGlu5 and selected compounds at rmGlu5 specified; Ki values of selected compounds at rmGlu5 disclosed. No in vivo data
FLIPR IC50 values of 40 compounds at hmGlu5 (27–8100 nM) and 12 compounds at rmGlu5 (25–132 nM) specified. x-ray structure of 24b. No in vivo data
Several formulation examples for compound 17a, including clinical studies with 18 healthy human volunteers
FLIPR IC50 values of 95 compounds at hmGlu5 (43–8400 nM) and 17 compounds at rmGlu5 (28–1370 nM) specified. No in vivo data
FLIPR IC50 values of 48 compounds at hmGlu5 (43–8100 nM) and 6 compounds at rmGlu5 (32–101 nM) specified. No in vivo data
receptor 5; MAO-B: Monoamine oxidase-B; mGluR: Metabotropic glutamate receptor; MPO: Multiparameter optimization; MW: Molecular weight; rmGlu5: Rat metabotropic glutamate receptor 5.
ALogP: Calculated value for the lipophilicity of a molecule expressed as log (octanol/water partition coefficient); FLIPR: Fluorescent imaging plate reader; GSH: Glutathione; hmGlu5: Human metabotropic glutamate
[130]
[129]
[123]
[125]
[124]
FLIPR IC50 values of approximately 100 compounds at hmGlu5 [127] (3–9800 nM) and rmGlu5 (2–1700 nM) and 19 compounds at hMAO-B (7 nM-100 mM) specified; GSH-adduct of selected compounds also disclosed. No in vivo data
[126]
[121]
[120]
Ref.
FLIPR IC50 values of 38 compounds at hmGlu5 (3–5421 nM) and 18 compounds at rmGlu5 (2–209 nM) specified. No in vivo data
FLIPR IC50 values of 10 compounds at hmGlu5 (24–330 nM) and 10 compounds at rmGlu5 (8–87 nM) specified; binding IC50 values of 9 compounds at rmGlu5 disclosed (42–275 nM) No in vivo data
FLIPR IC50 values of 13 compounds at hmGlu5 (86–140 nM) and 12 compounds at rmGlu5 (30–182 nM) specified; binding IC50 values of 10 compounds at rmGlu5 disclosed (43–1980 nM). No in vivo data
Disclosed data†
CHO-K1 cell line expressing hmGlu5 or rmGlu5 was used in fluorescent imaging plate reader mGlu5 functional assay. Rat cortical membranes were used in [3H]-M-2-methyl-6-(phenylethynyl)pyridine binding assay.
290 ± 39 3.8 ± 0.8
327 ± 22 2.6 ± 0.7
417 ± 40 2.9 ± 0.7
349 ± 22 3.0 ± 0.8
282 ± 21 3.0 ± 0.8
308 ± 20 3.1 ± 0.6
371 3.0
5.0 ± 0.8
5.4 ± 0.4
4.6 ± 0.7
MPO ± SD % in Golden Triangle
Insect Hi5 cell line expressing human monoamine oxidase B (hMAO-B) was used for hMAO-B functional assay.
†
WO2012172093A1 Dihydroindolizine Markush structure 25; 173 derivatives as mGluR supporting compounds inclcuding modulators racemates and enantiomers
Pyrazolopyrimidines, 397 ± 42 a process for their 1.9 ± 0.9 preparation and their use as medicine
WO2009095254A1 Markush structure 19; 492 supporting compounds including racemates and enantiomers
401 ± 42 3.5 ± 0.9
6-halo-pyrazolo-[1,5a]-pyridines, a process for their preparation and their use as mGluR modulators
WO2009095253A1 Markush structure 18; 1719 supporting compounds including racemates and enantiomers
MW ± SD ALogP ± SD
Original title
Patent number and compound information
Table 3. Summary of Merz patent applications.
Patent Review Li, Jørgensen & Campbell
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Pharm. Pat. Analyst (2013) 2(6)
35
68
49
28
30
% in Golden Triangle
[132]
In vitro: Ki values of 5 compounds disclosed; FLIPR IC50 values of 150 compounds at hmGlu5 or rmGlu5 reported as ranging from 2.2 to 5100 nM. In vivo: data of one compound in the MB test in mice and three compounds in the Vogel test in rats reported
Ki values of exemplified compounds at hmGlu5 reported as ranging from 1.8 to 1500 nM (specific data for 15 compounds); FLIPR IC50 values of 13 compounds at hmGlu5 presented. No in vivo data
Ki and FLIPR IC50 values of 10 compounds at hmGlu5 specified. No in vivo data
receptor 5.
MB: Marble burying; mGluR: Metabotropic glutamate receptor; MPO: Multiparameter optimization; MPEP: 2-methyl-6-(phenylethynyl)pyridine; MW: Molecular weight; rmGlu5: Rat metabotropic glutamate
[135]
[134]
[133]
[131]
In vitro: rat Ki values of 18 compounds reported as ranging from 6 to 700 nM (specific data for 2 compounds); FLIPR IC50 values of 255 compounds reported as ranging from 0.4 to 1800 nM at hmGlu5 or rmGlu5 (no specific data). In vivo: Efficacious doses of 17 compounds in the MB test in mice and 6 compounds in the GS test in rats reported
Ki values of five compounds at hmGlu5 specified; FLIPR IC50 values of 135 compounds at hmGlu5 or rmGlu5 reported as ranging from 0.4 to 4700 nM. No in vivo data
Ref.
Disclosed data†
HEK-293 cell line expressing hmGlu5 or rat mGlu5 was used in fluorescent imaging plate reader functional and [3H]-MPEP binding assays.
5.1 ± 0.5
5.1 ± 0.3
4.9 ± 0.6
5.1 ± 0.5
4.4 ± 0.6
MPO ± SD
ALogP: Calculated value for the lipophilicity of a molecule expressed as log (octanol/water partition coefficient); GS: Geller Seifter test; GSH: Glutathione; hmGlu5: Human metabotropic glutamate receptor 5;
†
WO2013040535A2 Bicarbocyclic and tricarbocyclic Markush structure ethynyl derivatives and uses of 30; 81 exemplified same compounds and 5 prophetic examples
357 ± 17 2.9 ± 0.6
379 ± 12 1.8 ± 0.9
WO2012088365A1 Markush structure 29; 187 supporting compounds
Bicyclo[3.2.1]octyl amide derivatives and uses of same
400 ± 30 2.3 ± 1.0
WO2011087758A1 Adamantyl amide derivatives Markush structure and uses of same 28; 135 exemplified compounds and 33 prophetic examples
296 ± 27 2.6 ± 0.7
WO2011053575A1 Spirolactam derivatives and use Markush structure of same 27; 159 exemplified compounds and 42 prophetic examples
MW ± SD ALogP ± SD
433 ± 35 2.1 ± 0.8
Original title
WO2010011570A1 Adamantyl diamide derivatives Markush structure and use of same 26; 257 exemplified compounds and 26 prophetic examples
Patent number and compound information
Table 4. Summary of Lundbeck patent applications.
mGlu5-negative allosteric modulators for the treatment of psychiatric & neurological disorders
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774
MPO: Multiparameter optimization; MW: Molecular weight.
In vitro mGlu5 functional activity was evaluated in aequorin assay using CHO cells expressing both hmGlu5 and aequorin. †
ALogP: Calculated value for the lipophilicity of a molecule expressed as log (octanol/water partition coefficient); hmGlu5: Human metabotropic glutamate receptor 5; mGluR5: Metabotropic glutamate receptor 5;
[140]
In vitro functional data not specified in detail but reported as pIC50 6.5–9.1. Specific value reported for 34a (pIC50 9.1). No in vivo data 374 ± 28 3.0 ± 0.6 Novel compounds WO2011151361A1 Markush structure 34; 52 supporting compounds
4.9 ± 0.4
23
[139]
In vitro functional data reported as IC50 4.5. Not specified for each compound. No in vivo data 65 5.4 ± 0.3 Use of thiazoloimidazoles, thiazolotetrazoles and thiazolotriazoles as mGluR5 antagonists WO2009087220A1 Markush structure 32; 65 supporting compounds
329 ± 24 2.7 ± 0.6
pIC50 4.9–9.0 . Not specified for each compound. No in vivo data 49 4.9 ± 0.7 Triazole amide derivatives for use in therapy WO2009115486A1 Markush structure 31; 43 supporting compounds
336 ± 26 3.3 ± 0.9
Disclosed data† MW ± SD MPO ± SD % in ALogP ± SD Golden Triangle Original title Patent number and compound information
Table 5. Summary of Glaxo patent applications.
[136]
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Patent Review
solubility. Incorporation of N in the A ring and NH2 at position of X increased solubility significantly but reduced activity at mGlu5 drastically, as demonstrated by representative compounds 11b & 11c (Figure 2). The remaining five compounds had IC50 values ranging from 146 to 1430 nM. The claims include the compounds of formula 11, exemplified compounds, pharmaceutical composition, and use for the treatment of a disorder or a disease in a subject mediated by mGlu5. The example compounds have high MPO scores and 89% of them are inside the Golden Triangle. The second application covered a series of prodrug analogs around mavoglurant aiming for improving bioavailability [111]. Despite relatively broad Markush structure 12 (Figure 2), only derivatives of mavoglurant were exemplified. The 95 different –OR7 included primarily esters derived from amino acids (31%), benzoic or nicotinic acids (18%), or simple aliphatic acids including fatty acids (37%). Some of these compounds were evaluated in an in vitro metabolic stability assay in human and rat liver microsomes that measured the intrinsic clearance (CLint) of the parent compound. Selected compounds were also characterized in a solubility assay in pH 6.8 buffer. Of the 12 prodrugs with human liver microsomal CLint data, only three, including compound 12a (Figure 2), had improved CLint relative to the parent mavoglurant (100 vs 51 µg/ml) but their human liver microsomal CLint was either comparable or higher relative to mavoglurant, such as with the pyrrolidinyl analog 12b (Figure 2). Plasma and brain exposure studies in rat were disclosed for prodrugs 12c & 12d (Figure 2). Neither had improved plasma and brain exposure of the parent compared with mavoglurant at 3 mg/kg, 1 h post p.o. dosing (plasma: 300 µg/ml
X2
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R3
13b 101% inhib. at 0.1 µM
Figure 2. Markush structures and representative compounds of Novartis applications. CLint: Intrinsic clearance; inhib.: Inhibition; LM: Liver microsomes.
FXS has been published [15,16]. Despite a small molecular footprint, the calculated physicochemical properties are relatively poor due to high lipophilicity, leading to a low average MPO score and
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Metabotropic glutamate receptor 5-negative allosteric modulators for the treatment of psychiatric and neurological disorders (2009–July 2013) Guiying Li*1, Morten Jørgensen2 & Brian M Campbell3 Negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu5) have been actively pursued for over a decade as a potential treatment for anxiety, depression, substance abuse, pain, levodopa-induced dyskinesia in Parkinson’s disease, fragile X Syndrome, autism, gastroesophageal reflux disease and lower-urinary-tract disorders. This article begins with an introduction of preclinical validation of potential therapies for psychiatric and neurological disorders, and of clinical results, followed by a comprehensive overview of the mGlu5-negative allosteric modulator patent applications published between 2009 and July 2013, with a focus on the analysis of structure and in silico CNS drug-like properties of example compounds and disclosed data. Given positive results in proof-ofconcept studies in humans for certain indications such as levodopa-induced dyskinesia in Parkinson’s disease, fragile X Syndrome, gastroesophageal reflux disease, migraine and anxiety, and the soaring chemical diversity among the mGlu5-negative allosteric modulators, there is reason to believe that a drug will emerge from this therapeutic class in the near future.
Glutamate is the primary excitatory neurotransmitter in the CNS acting on both ionotropic and metabotropic glutamate (mGlu) receptors. mGlu receptors belong to the class C of G-protein-coupled receptor superfamily and are divided into three groups and eight subtypes based on homology, pharmacology and signal transduction mechanisms: group I (mGlu1,5), group II (mGlu 2,3) and group III (mGlu4,6,7,8) [1]. mGlu5 is located primarily on neuronal postsynaptic excitatory terminals and glia, coupled to Gq/11 protein and activate phospholipase C resulting in increased intracellular calcium release [2]. mGlu5 is highly expressed in the CNS and is concentrated in the cortex, hippocampus, and basal ganglia, regions important in many neurological and psychiatric disorders [3,4]. This receptor has important functions in regulating neuronal development and synaptic maintenance, which has led to the prediction of its involvement in a variety of CNS-related disorders [5–7]. Selective orthosteric ligands for mGlu receptors have been challenging to find, although a few exist [8,9]. Because of this, much of the work done to delineate the role of mGlu5 in CNS physiology has focused on allosteric modulators. A wealth of preclinical data supporting the therapeutic potential of mGlu5-negative allosteric modulators (NAMs) for treating CNS disorders were summarized in recent reviews [5,6], including beneficial effects of extensively used tools 2-methyl6-(phenylethynyl)pyridine (MPEP) (Figure 1; 1), 3-([2-methyl-4-thiazolyl]ethynyl)pyridine (Figure 1, 2) and fenobam (Figure 1; 3) in animal models of fragile X syndrome (FXS) (e.g., fragile X mental retardation 1 [Fmr1]-mutant mice), Parkinson’s disease (PD) and levodopa (l-DOPA)-induced dyskinesia in PD (PD-LID)
10.4155/PPA.13.58 © 2013 Future Science Ltd
Pharm. Pat. Analyst (2013) 2(6), 767–802
Discovery Chemistry & DMPK, Lundbeck Research USA, 215 College Rd., Paramus, NJ 07661, USA 2 Discovery Chemistry & DMPK, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark 3 Neuroinflammation, Lundbeck Research USA, 215 College Rd., Paramus, NJ 07661, USA *Author for correspondence: Tel.: +1 201 350 0140 Fax: +1 201 261 0623 E-mail: [email protected] 1
ISSN 2046-8954
767
Patent Review
Li, Jørgensen & Campbell
(reversal of motor impairments in rodents or primates treated with Orthosteric ligands: Compounds 6-hydroxydopamine (6-OHDA) or that bind to the same site as the 1-methyl-4-phenyl-1,2,3,6-tetrareceptor’s endogenous ligand hydropyridine), anxiety (e.g., fear (e.g., glutamate). potentiated startle, contextual fear Allosteric modulators: Ligands conditioning, Vogel conflict drinkthat bind to a site that is ing, Geller Seifter [GS] test, stresstopographically distinct from the orthosteric binding site. induced hyperthermia [SIH], elevated plus maze, defensive marble Negative allosteric modulators: burying [MB]), substance abuse Ligands that bind to an allosteric sites and inhibit the action of the (e.g., drug self-administration and orthosteric agonists (e.g., conditioned-place preference) and glutamate). The negative chronic pain (e.g., allodynia modmodulator attenuates the effects els). Preclinical studies of newer seof the orthosteric ligand without lective compounds with improved triggering a functional activity on drug-like properties such as MRZits own in the absence of the 8676 (Figure 1; 4), 2-chloro-4-([2,5orthosteric ligand. dimethyl-1-(4-[trif luoromethoxy] Golden Triangle: Triangular phenyl)-1H-imidazol-4-yl]ethyshaped area defined by plotting nyl)pyridine (CTEP) (Figure 1; molecular weight (MW) versus 5), and GRN-529 (Figure 1; 6), cLogD7.4 with a base-line from as well as front-running agents LogD = -2.0 to LogD = 5.0 at in the clinic such as mavoglurant MW = 200 and an apex at LogD = 1.5 and MW = 450. (Figure 1; AFQ056, 7), and dipraglu Compounds inside this area tend rant (Figure 1; ADX48621, 8), were to have a higher probability of published recently. Mavoglurant, success in achieving good dipraglurant, and MRZ-8676 were metabolic stability and shown to alleviate dyskinetic-like membrane permeability than behaviors in animals where dopathose outside of the area based mine neurons had been ablated on an analysis by Pfizer scientists. with neurotoxic agents such as Multiparameter optimization 6-OHDA or 1-methyl-4-phenylscore: Desirability function based 1,2,3,6-tetrahydropyridine [10–12]. on six in silico physicochemical In Fmr1 knockout mice, a model of parameters (molecular weight, FXS, mavoglurant rescued deficits ALogP, cLogD7.4, topological polar surface area, number of H bond in prepulse inhibition and social donors and pKa). This score ranges behaviors [13,14]. In the same model, from 0 (lowest) to 6 (highest). A CTEP showed comprehensive phescore ≥4 is indicative of good CNS notype correction including reverdrug-like properties. sal of elevated hippocampal longterm depression, protein synthesis, and audiogenic seizures after acute treatment. CTEP also rescued cognitive deficits, auditory hypersensitivity, aberrant dendritic spine density, overactive ERK and mTOR signaling, and partially corrected macroorchidism following chronic administration [15]. In addition, this compound demonstrated anxiolytic-like activity in SIH in mice and Vogel conflict drinking in rats [16]. In mouse models of autism, GRN-529 alleviated multiple behavior symptoms of autism including repetitive behaviors, spontaneous stereotyped jumping and lack of sociability [17]. Although more limited in scope, mGlu5 NAMs also show antidepressant efficacy Key terms
768
in tail suspension assay and forced swim test as was recently shown with GRN-529 [18]. With the plethora of preclinical data supporting the potential efficacy of mGlu5 NAMs in human disease and evidence of mGlu5 signaling dysregulation in a range of CNS pathologies [5], it is no surprise that significant efforts have been made to develop drug-like molecules for testing the clinical efficacy of this target. In recent years, at least nine mGlu5 NAMs have entered into clinical studies [19], of which at least four (mavoglurant, dipraglurant, RO4917523 [RG7090] [Figure 1; 9] and fenobam) continue to be actively pursued. Proof-of-concept in patients was achieved for several indications including PD-LID with mavoglurant [20] and dipraglurant [201], gastroesophageal reflux disease (GERD) and migraine with raseglurant (Figure 1; 10) [21,22], and anxiety with fenobam [23]. Results in FXS have been less straight forward. Mavoglurant was not effective in treating symptoms in a broad cohort of FXS patients [24], however, in a secondary analysis, patients with full methylation of the Fmr1 gene promoter showed significant improvement, supporting efficacy by mGlu5 NAMs in a subpopulation of this indication as well. Fenobam was also evaluated in an open label trial in FXS patients where it reduced prepulse inhibition in these patients indicating the potential for a beneficial effect on sensory gaiting [25]. With substantial preclinical support, as well as encouraging proof-of-concept clinical data, a great deal of effort has gone into discovering new mGlu5 NAM drug candidates in recent years. Companies have also tried to improve the developability and drug efficacy via formulation or prodrug approaches. This article provides a comprehensive overview of patent applications published between 2009 and July 2013 and focuses on the analysis of structure, in silico CNS drug-like properties such as the Golden Triangle [26] and multiparameter optimization (MPO) score [27], and disclosed data of supporting compounds. Patent analysis (publications during 2009 & July 2013)
Approximately 190 mGlu5 NAM patent applications have been published since 2000. The scope of this article is to analyze the structures, drug-like properties and biological data of mGlu5 NAMs in 66 patent applications that appeared between 2009 and July 2013. The drug-like property analysis was based on a number of molecular descriptors as follows: molecular weight (MW); ALogP (calculated value for the lipophilicity of a molecule expressed as log [octanol/water partition coefficient]); cLogD 7.4 (calculated value for the lipophilicity of a molecule expressed as log [octanol/aqueous buffer at pH 7.4 distribution coefficient]); topological
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mGlu5-negative allosteric modulators for the treatment of psychiatric & neurological disorders
polar surface area; number of H bond donors; and basic pK a (basicity of the most basic center). These parameters were calculated using Pipeline Pilot components (v8.5) and then used for the MPO and Golden Triangle analyses. The average MW, ALogP and MPO scores ± SD, and percentage of the compounds inside the Golden Triangle of the example compounds from each application are listed in the summary Tables 1–9. The mGlu5 NAMs outside the scope of this article, either in patent applications or in the primary literature, have been previously discussed in several reviews [9,28–30].
N
N
S
N
N O 2 MTEP
1 MPEP
O
Cl
O
3 Fenobam, Phase I/II N
N
H N
N NH
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OCF3 N
Cl
N 5 CTEP
4 MRZ-8676 O
N
N
O
O
H
N
■■ Novartis AG
H OH
Novartis published nine patent apOCHF2 7 Mavoglurant (AFQ056) plications during 2009–2012 with 6 Phase II/III focus on utility and improvement GRN-529 in drug properties and/or developN ability of their previously patented N F lead series especially the mavoglurant chemotype. The patent numN Cl N ber, compound information, title, N CNS drug-likeness and disclosed N F 9 data are summarized in Table 1. RO4917523 (RG7090) 8 Phase II There are three patent applicaDipraglurant (ADX48621) tions covering the use of the comPhase II pounds within Markush structures NH2 in previous applications [101–103]. F The first application claiming the N use of mGlu5 modulators for the 10 treatment, prevention or delay of Raseglurant (ADX10059) progression of PD appeared in discontinued 2009 [104]. An unspecific compound A was reported to potentiFigure 1. Metabotropic glutamate receptor 5-negative allosteric modulators in vivo tools and ate the antiparkinsonian response example clinical compounds. of low dose l-DOPA at 25 mg/kg, CTEP: 2-chloro-4-([2,5-dimethyl-1-(4-[trifluoromethoxy]phenyl)-1H-imidazol-4-yl]ethynyl)pyridine; peroral (p.o.) after either acute or MPEP: 2-methyl-6-(phenylethynyl)pyridine; MTEP: 3-([2-methyl-4-thiazolyl]ethynyl)pyridine. repeated administration. The second application claiming the use of an mGlu5 modulator for the treatment, prevention the company’s development compound mavoglurant, or delay of progression of a pervasive developmental was disclosed to have antidyskinetic effect in combinadisorder such as FXS and fragile X-associated tremor/ tion with l-DOPA in human patients and in parkinsoataxia syndrome was also published in 2009 [105]. The nian monkeys. Detailed studies have been reported in third application claiming the use of an mGlu modu- primary papers [10,20]. None of the three applications lator in combination with at least one of l-DOPA, a claimed any specific compounds. A fourth use patDOPA decarboxylase inhibitor, a catechol-O-methyl ent application claiming combinations of a7 nicotinic transferase inhibitor or a dopamine agonist was pub- acetylcholine receptor activators and mGlu5 antagolished in 2010 [106]. An unspecific compound A, likely nists for treating PD-LID was published in 2012 [107].
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Pharm. Pat. Analyst (2013) 2(6)
769
770
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4-tolyl-ethynyl-octahydo-indole-1-ester derivatives
WO2012101058A1 Prodrug Markush structure 12; 95 supporting compounds
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Ltk-cells expressing hmGlu5 were used in in vitro mGlu5 functional assays.
Combinations of a7 nicotinic acetylcholine NA receptor activators and mGluR5 antagonists for use in dopamine induced dyskinesia in Parkinson’s disease
441 ± 39 4.6 ± 1.5
NA
3.7 ± 0.7
5.3 ± 0.5
5.1
5.1
NA
3.5 ± 0.3
NA
NA
NA
0
89
100
100
NA
0
NA
NA
[107]
[111]
In vitro human/rat liver microsomal CLint and solubility of selected compounds; plasma and brain exposure of two prodrugs and mavoglurant
In vitro a7-nAChR activity of three selected compounds; effect of MPEP, JN403 and combination of these two compounds in parkinsonian primates
[110]
[108]
FMRP mRNA transcript, FMRP protein level, or Fmr1 gene methylation IC50 values of 9 compounds at hmGlu5 (16–1430 nM) and solubility at pH 6.8 of these compounds specified. No in vivo data
[109]
[106]
[112]
[105]
[104]
Ref.
No biological data
Antidyskinetic effect of an unspecified compound in combination with l-DOPA in human patients and parkinsonian primates
Percentage inhibition of inositol phosphonate turnover at 0.1 µM. No in vivo data
No specific data
Antidyskinetic effect of an unspecified compound in parkinsonian primates
MPO ± SD % in Disclosed data† Golden Triangle
glutamate receptor 5; l-DOPA: Levodopa; MPEP: 2-methyl-6-(phenylethynyl)pyridine; MPO: Multiparameter optimization; MW: Molecular weight; NA: Not analyzed.
ALogP: Calculated value for the lipophilicity of a molecule expressed as log (octanol/water partition coefficient); CLint: Intrinsic clearance; FMRP: Fragile-X mental retardation protien; hmGlu5: Human metabotropic
†
WO2012127393A1 Use patent
4-(hetero)aryl-ethynyl-octahydro-indole1-carboxylic acid esters
WO2012084873A1 Markush structure 11; 9 supporting compounds
321 ± 9 2.6 ± 0.6
Predictive markers useful in the treatment 313 of fragile X syndrome. 3.3
WO2011137206A1 Mavoglurant
313 3.3
NA
403 ± 29 5.9 ± 0.8
Processes for the preparation of 4-oxooctahydro-indole-1-carboxylic acid methyl ester and derivatives thereof
Combination products
Organic compounds
NA
NA
MW ± SD ALogP ± SD
WO2010018154A1 Mavoglurant
[101–103]
WO2010000763A2 Use patent covering compounds in
US20090105266 Markush structure 13; 127 supporting compounds
[101–103]
WO2009047303A2 Use patent covering compounds in
Organic compounds
Organic compounds
WO2009047296A2 Use patent covering compounds in
[101–103]
Original title
Patent number and compound information
Table 1. Summary of Novartis patent applications.
Patent Review Li, Jørgensen & Campbell
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Pharm. Pat. Analyst (2013) 2(6)
mGluR5: Metabotropic glutamate receptor 5; MPO: Multiparameter optimization; MW: Molecular weight.
Epstein-Barr nuclear antigen cell membranes expressing hmGlu5 were used in a [3H]-2-methyl-6-(phenylethynyl)pyridine binding assay.
ALogP: Calculated value for the lipophilicity of a molecule expressed as log (octanol/water partition coefficient); GERD: Gastroesophageal reflux disease; hmGlu5: Human metabotropic glutamate receptor 5;
†
[117]
In vitro dissolution profile of various compositions of RO4917523 in simulated gastric fluid and simulated intestinal fluid. PK of RO4917523 in cynomolgus monkeys following different immediate and modified release formulation Pharmaceutical compositions of mGluR5 antagonists WO2012019990A2 Markush structure 14; 45 supporting compounds
367 ± 32 5.0 ± 0.9
3.3 ± 0.8
2
[116]
In vitro dissolution profile of various compositions of RO4917523 in simulated gastric fluid and simulated intestinal fluid. PK of RO4917523 in cynomolgus monkeys following different immediate and modified release formulation Pharmaceutical compositions of mGluR5 antagonists WO2012019989A2 Markush structure 14; 45 supporting compounds
367 ± 32 5.0 ± 0.9
3.3 ± 0.8
2
[115]
Ki values of 57 compounds at hmGlu5 specified (33–817 nM). No in vivo data 81 5.6 ± 0.3 Imidazole derivatives as mGluR5 antagonists WO2011006910A1 Markush structure 15; 57 supporting compounds
337 ± 24 2.4 ± 0.5
[118]
Ki values of 40 compounds at hmGlu5 (5–109 nM). No in vivo data 98 5.5 ± 0.4 Pyridine-2-ylcarboxylic acid amides WO2010100050A1 Markush structure 16; 53 supporting compounds
274 ± 21 2.4 ± 0.7
[114]
Ki values of 28 compounds at hmGlu5 (5–211 nM) specified. No in vivo data 2 3.3 ± 0.8 Use of mGluR5 antagonists for the treatment of GERD WO2009024491A1 Markush structure 14; 43 supporting compounds
361 ± 54 5.0 ± 1.2
Disclosed data† MPO ± SD % in Golden Triangle Original title
MW ± SD ALogP ± SD
Patent Review
Patent number and compound information
Table 2. Summary of Roche patent applications
These claims were supported by improved antiparkinsonian scores when using the combination of MPEP and nAChR a7-selective agonist JN403 ([S]-[1-azabicyclo(2.2.2)oct-3-yl]-carbamic acid [S]-1-[2-fluoro-phenyl]-ethyl ester) relative to each compound alone in Parkinsonian primates. Two mGlu5 NAMs, MPEP and 2-([1S,2S]-2-carboxycyclopropyl)-3-(9Hxanthen-9-yl)-d-alanine (LY341495) were specifically claimed [31]. A patent application concerning predictive markers useful in the treatment of FXS was published in 2011 in which mavoglurant was specifically claimed as a treatment agent [108]. The invention was based on the finding that the methylation status of the Fmr1 gene region and/or a reduction in the level of Fmr1 gene expression along with FMRP, the translational product of the gene, can be used to predict responsiveness to mGlu5 treatment in patients with FXS. Results of the clinical trial along with the secondary data analysis were published [24]. Further patent estate related to mavoglurant includes an invention related to the processes for the preparation of mavoglurant and derivatives, which was published in 2010 [109]. It claimed production and use of mavoglurant, intermediates and salt forms. Efforts to improve developability of mavoglurant series were described in two patent applications published in 2012. The first application related to a series of 4-(hetero)aryl-ethynyl-octahydro-indole-1-carboxylic acid esters with improved solubility [110]. The application specifically mentioned that there is a need for mGlu5 antagonists that are good drug candidates possessing the following attributes: low binding to plasma proteins, good absorption from the GI tract, sufficient metabolic stability, favorable PK profile for a long-lasting blood exposure after oral administration while avoiding an overly high maximum plasma concentration (Cmax), nonhygroscopicity, easy formulation, lack of toxicity and fewer side effects. Furthermore, good solubility in water was specifically highlighted for drugs intended for pediatric uses (e.g., with infant FXS patients). Of the nine exemplified compounds of formula 11 (Figure 2), seven have X as OH; and two have X as NH2; eight have R1 as Me, and one has R1 as Et. Ring A is 3-chlorophenyl, m-tolyl (in two compounds), 5-methylpyridin-3-yl, 2-methylpyridin-4-yl, 6-methylpyridin-2-yl, 2-chloropyridin-4-yl, 4-methylpyridin-2-yl or 2-methylthiazol-4-yl. All nine compounds were evaluated for efficacy in a calcium mobilization functional assay against human mGlu5 (hmGlu5), which was expressed in Ltk-cells. The solubility of eight compounds in chloride-free phosphate buffer (pH 6.8) was determined. Representative compound 11a (Figure 2) was the most potent with decent
Ref.
mGlu5-negative allosteric modulators for the treatment of psychiatric & neurological disorders
771
772
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Pyrazolopyrimidines, 285 ± 46 a process for their 3.2 ± 1.1 preparation and their use as medicine Crystalline forms of substituted pyrazolopyrimidines mGluR modulators
mGluR modulators
mGluR modulators
Enteric formulations of mGluR modulators mGluR modulators
WO2010063487A1 Markush structure 22; 188 supporting compounds
WO2011064237A1 Compound 17a
WO2012052451A1 Markush structure 23; 131 supporting compounds
WO2012085166A1 Markush structure 20; 48 supporting compounds
WO2012085167A1 Markush structure 21; 95 supporting compounds
WO2012139876A1 Markush structure 17; 242 supporting compounds
WO2012152854A1 Markush structure 24; 40 supporting compounds
future science group
4.1 ± 0.8
5.4 ± 0.5
5.0 ± 0.6
5.1 ± 0.5
5.0 ± 0.7
4.9 ± 0.5
5.4
50
80
15
45
83
63
0
76
54
15
[122]
No in vitro and in vivo biological data
FLIPR EC50 or IC50 values of all exemplified compounds at hmGlu5 and selected compounds at rmGlu5 specified; Ki values of selected compounds at rmGlu5 disclosed. No in vivo data
FLIPR IC50 values of 40 compounds at hmGlu5 (27–8100 nM) and 12 compounds at rmGlu5 (25–132 nM) specified. x-ray structure of 24b. No in vivo data
Several formulation examples for compound 17a, including clinical studies with 18 healthy human volunteers
FLIPR IC50 values of 95 compounds at hmGlu5 (43–8400 nM) and 17 compounds at rmGlu5 (28–1370 nM) specified. No in vivo data
FLIPR IC50 values of 48 compounds at hmGlu5 (43–8100 nM) and 6 compounds at rmGlu5 (32–101 nM) specified. No in vivo data
receptor 5; MAO-B: Monoamine oxidase-B; mGluR: Metabotropic glutamate receptor; MPO: Multiparameter optimization; MW: Molecular weight; rmGlu5: Rat metabotropic glutamate receptor 5.
ALogP: Calculated value for the lipophilicity of a molecule expressed as log (octanol/water partition coefficient); FLIPR: Fluorescent imaging plate reader; GSH: Glutathione; hmGlu5: Human metabotropic glutamate
[130]
[129]
[123]
[125]
[124]
FLIPR IC50 values of approximately 100 compounds at hmGlu5 [127] (3–9800 nM) and rmGlu5 (2–1700 nM) and 19 compounds at hMAO-B (7 nM-100 mM) specified; GSH-adduct of selected compounds also disclosed. No in vivo data
[126]
[121]
[120]
Ref.
FLIPR IC50 values of 38 compounds at hmGlu5 (3–5421 nM) and 18 compounds at rmGlu5 (2–209 nM) specified. No in vivo data
FLIPR IC50 values of 10 compounds at hmGlu5 (24–330 nM) and 10 compounds at rmGlu5 (8–87 nM) specified; binding IC50 values of 9 compounds at rmGlu5 disclosed (42–275 nM) No in vivo data
FLIPR IC50 values of 13 compounds at hmGlu5 (86–140 nM) and 12 compounds at rmGlu5 (30–182 nM) specified; binding IC50 values of 10 compounds at rmGlu5 disclosed (43–1980 nM). No in vivo data
Disclosed data†
CHO-K1 cell line expressing hmGlu5 or rmGlu5 was used in fluorescent imaging plate reader mGlu5 functional assay. Rat cortical membranes were used in [3H]-M-2-methyl-6-(phenylethynyl)pyridine binding assay.
290 ± 39 3.8 ± 0.8
327 ± 22 2.6 ± 0.7
417 ± 40 2.9 ± 0.7
349 ± 22 3.0 ± 0.8
282 ± 21 3.0 ± 0.8
308 ± 20 3.1 ± 0.6
371 3.0
5.0 ± 0.8
5.4 ± 0.4
4.6 ± 0.7
MPO ± SD % in Golden Triangle
Insect Hi5 cell line expressing human monoamine oxidase B (hMAO-B) was used for hMAO-B functional assay.
†
WO2012172093A1 Dihydroindolizine Markush structure 25; 173 derivatives as mGluR supporting compounds inclcuding modulators racemates and enantiomers
Pyrazolopyrimidines, 397 ± 42 a process for their 1.9 ± 0.9 preparation and their use as medicine
WO2009095254A1 Markush structure 19; 492 supporting compounds including racemates and enantiomers
401 ± 42 3.5 ± 0.9
6-halo-pyrazolo-[1,5a]-pyridines, a process for their preparation and their use as mGluR modulators
WO2009095253A1 Markush structure 18; 1719 supporting compounds including racemates and enantiomers
MW ± SD ALogP ± SD
Original title
Patent number and compound information
Table 3. Summary of Merz patent applications.
Patent Review Li, Jørgensen & Campbell
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Pharm. Pat. Analyst (2013) 2(6)
35
68
49
28
30
% in Golden Triangle
[132]
In vitro: Ki values of 5 compounds disclosed; FLIPR IC50 values of 150 compounds at hmGlu5 or rmGlu5 reported as ranging from 2.2 to 5100 nM. In vivo: data of one compound in the MB test in mice and three compounds in the Vogel test in rats reported
Ki values of exemplified compounds at hmGlu5 reported as ranging from 1.8 to 1500 nM (specific data for 15 compounds); FLIPR IC50 values of 13 compounds at hmGlu5 presented. No in vivo data
Ki and FLIPR IC50 values of 10 compounds at hmGlu5 specified. No in vivo data
receptor 5.
MB: Marble burying; mGluR: Metabotropic glutamate receptor; MPO: Multiparameter optimization; MPEP: 2-methyl-6-(phenylethynyl)pyridine; MW: Molecular weight; rmGlu5: Rat metabotropic glutamate
[135]
[134]
[133]
[131]
In vitro: rat Ki values of 18 compounds reported as ranging from 6 to 700 nM (specific data for 2 compounds); FLIPR IC50 values of 255 compounds reported as ranging from 0.4 to 1800 nM at hmGlu5 or rmGlu5 (no specific data). In vivo: Efficacious doses of 17 compounds in the MB test in mice and 6 compounds in the GS test in rats reported
Ki values of five compounds at hmGlu5 specified; FLIPR IC50 values of 135 compounds at hmGlu5 or rmGlu5 reported as ranging from 0.4 to 4700 nM. No in vivo data
Ref.
Disclosed data†
HEK-293 cell line expressing hmGlu5 or rat mGlu5 was used in fluorescent imaging plate reader functional and [3H]-MPEP binding assays.
5.1 ± 0.5
5.1 ± 0.3
4.9 ± 0.6
5.1 ± 0.5
4.4 ± 0.6
MPO ± SD
ALogP: Calculated value for the lipophilicity of a molecule expressed as log (octanol/water partition coefficient); GS: Geller Seifter test; GSH: Glutathione; hmGlu5: Human metabotropic glutamate receptor 5;
†
WO2013040535A2 Bicarbocyclic and tricarbocyclic Markush structure ethynyl derivatives and uses of 30; 81 exemplified same compounds and 5 prophetic examples
357 ± 17 2.9 ± 0.6
379 ± 12 1.8 ± 0.9
WO2012088365A1 Markush structure 29; 187 supporting compounds
Bicyclo[3.2.1]octyl amide derivatives and uses of same
400 ± 30 2.3 ± 1.0
WO2011087758A1 Adamantyl amide derivatives Markush structure and uses of same 28; 135 exemplified compounds and 33 prophetic examples
296 ± 27 2.6 ± 0.7
WO2011053575A1 Spirolactam derivatives and use Markush structure of same 27; 159 exemplified compounds and 42 prophetic examples
MW ± SD ALogP ± SD
433 ± 35 2.1 ± 0.8
Original title
WO2010011570A1 Adamantyl diamide derivatives Markush structure and use of same 26; 257 exemplified compounds and 26 prophetic examples
Patent number and compound information
Table 4. Summary of Lundbeck patent applications.
mGlu5-negative allosteric modulators for the treatment of psychiatric & neurological disorders
Patent Review
773
774
MPO: Multiparameter optimization; MW: Molecular weight.
In vitro mGlu5 functional activity was evaluated in aequorin assay using CHO cells expressing both hmGlu5 and aequorin. †
ALogP: Calculated value for the lipophilicity of a molecule expressed as log (octanol/water partition coefficient); hmGlu5: Human metabotropic glutamate receptor 5; mGluR5: Metabotropic glutamate receptor 5;
[140]
In vitro functional data not specified in detail but reported as pIC50 6.5–9.1. Specific value reported for 34a (pIC50 9.1). No in vivo data 374 ± 28 3.0 ± 0.6 Novel compounds WO2011151361A1 Markush structure 34; 52 supporting compounds
4.9 ± 0.4
23
[139]
In vitro functional data reported as IC50 4.5. Not specified for each compound. No in vivo data 65 5.4 ± 0.3 Use of thiazoloimidazoles, thiazolotetrazoles and thiazolotriazoles as mGluR5 antagonists WO2009087220A1 Markush structure 32; 65 supporting compounds
329 ± 24 2.7 ± 0.6
pIC50 4.9–9.0 . Not specified for each compound. No in vivo data 49 4.9 ± 0.7 Triazole amide derivatives for use in therapy WO2009115486A1 Markush structure 31; 43 supporting compounds
336 ± 26 3.3 ± 0.9
Disclosed data† MW ± SD MPO ± SD % in ALogP ± SD Golden Triangle Original title Patent number and compound information
Table 5. Summary of Glaxo patent applications.
[136]
Li, Jørgensen & Campbell
Ref.
Patent Review
solubility. Incorporation of N in the A ring and NH2 at position of X increased solubility significantly but reduced activity at mGlu5 drastically, as demonstrated by representative compounds 11b & 11c (Figure 2). The remaining five compounds had IC50 values ranging from 146 to 1430 nM. The claims include the compounds of formula 11, exemplified compounds, pharmaceutical composition, and use for the treatment of a disorder or a disease in a subject mediated by mGlu5. The example compounds have high MPO scores and 89% of them are inside the Golden Triangle. The second application covered a series of prodrug analogs around mavoglurant aiming for improving bioavailability [111]. Despite relatively broad Markush structure 12 (Figure 2), only derivatives of mavoglurant were exemplified. The 95 different –OR7 included primarily esters derived from amino acids (31%), benzoic or nicotinic acids (18%), or simple aliphatic acids including fatty acids (37%). Some of these compounds were evaluated in an in vitro metabolic stability assay in human and rat liver microsomes that measured the intrinsic clearance (CLint) of the parent compound. Selected compounds were also characterized in a solubility assay in pH 6.8 buffer. Of the 12 prodrugs with human liver microsomal CLint data, only three, including compound 12a (Figure 2), had improved CLint relative to the parent mavoglurant (100 vs 51 µg/ml) but their human liver microsomal CLint was either comparable or higher relative to mavoglurant, such as with the pyrrolidinyl analog 12b (Figure 2). Plasma and brain exposure studies in rat were disclosed for prodrugs 12c & 12d (Figure 2). Neither had improved plasma and brain exposure of the parent compared with mavoglurant at 3 mg/kg, 1 h post p.o. dosing (plasma: 300 µg/ml
X2
Patent Review
R3
13b 101% inhib. at 0.1 µM
Figure 2. Markush structures and representative compounds of Novartis applications. CLint: Intrinsic clearance; inhib.: Inhibition; LM: Liver microsomes.
FXS has been published [15,16]. Despite a small molecular footprint, the calculated physicochemical properties are relatively poor due to high lipophilicity, leading to a low average MPO score and
