Patent Review
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GPR119 agonists 2009–2011 Daniel J Buzard*, Juerg Lehmann, Sangdon Han & Robert M Jones The increasing incidence of Type II diabetes mellitus worldwide continues to attract the attention and resources of the pharmaceutical industry in the pursuit of more effective therapies for blood glucose control. New approaches that compare favorably with classical medicaments while avoiding hypoglycemic episodes or waning effectiveness are paramount. Recent advances toward this end have been realized based on the biology of the glucagon like peptide-1 receptor (GLP1R). This b-cell-expressed GPCR has the ability to promote insulin release in a glucose-dependent fashion, and has been shown to elicit improved glycemic control and preservation of b-cell mass. Direct activation of GLP1R utilizing peptide mimetics has been achieved; however, attempts to access the biology of this receptor via small-molecule approaches have thus far been elusive. In this context, GPR119 has emerged as a tractable new alternative to GLP1R. GPR119 is another GPCR expressed on the b-cell, which, like GLP1R, signals in a glucose-dependent manner. Moreover, GPR119-mediated increases in GLP-1 and other incretins upon activation in the intestine further increase the insulinotropic activity of the b-cell. The early success in identifying small-molecule agonists of the GPR119 has prompted a rapid increase in the number of patent applications filed in the last few years. In this review we provide a comprehensive summary of all patent activity in this field that has appeared within the 2009–2011 timeframe. Type II diabetes mellitus remains a global epidemic; in the USA alone, 25.8 million
individuals have been diagnosed with the disease [201] . Worldwide, this number exceeds 171 million and is projected to double over the next several decades [1] . Uncontrolled hyperglycemia in these individuals results in complications such as heart disease and stroke, blindness, kidney disease, nervous system disease and increased mortality. Lifestyle modification can delay the onset and severity of Type II diabetes, but pharmacological intervention is frequently required to manage hyperglycemia uncontrolled by diet or exercise. The development of new therapeutics targeting the b-cell-expressed glucagonlike peptide-1 receptor (GLP1R) has greatly increased the options available to patients and physicians [2] . Activation of this GPCR leads to an increase in insulin output in response to rising glucose levels, and therefore an improvement in glycemic control. This outcome has been exploited by the development of dipeptidyl peptidase-4 (DPP-IV) inhibitors, which block GLP-1 degradation (e.g., Januvia®). GLP-1 mimetics, or glutides, such as Byetta®, have also been successful in helping patients achieve glucose control, although these approaches have required injectable peptide formulations due to the difficulty thus far in identifying orally bioavailable small-molecule GLP1R agonists. GPR119 is another GPCR expressed on the b-cell that, when activated, stimulates insulin release in response to rising levels of glucose via a Gas-mediated increase in cAMP [3] . In addition to GPR119 signaling on the b-cell, these agonists also elevate GLP-1, GIP and PYY levels through activation of GPR119 expressed on intestinal enteroendocrine cells. Elevated levels of these incretins, in turn, activate their cognate receptors on the b-cell and elsewhere, affording additional insulin secretion. Thus, the biology of GPR119 entails two complementary mechanisms for glucose control.
10.4155/PPA.12.33 © 2012 Future Science Ltd
Pharm. Pat. Analyst (2012) 1(3), 285–299
Department of Medicinal Chemistry, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA, *Author for correspondence: Tel.: +1 858 453 7200 E-mail: [email protected]
ISSN 2046-8954
285
Patent Review
Buzard, Lehmann, Han & Jones
Compared to GLP1R, GPR119 has been much more amenable to Type II diabtes mellitus: Adultsmall-molecule approaches aimed onset or non-insulin-dependent at accessing the biology of this rediabetes. Characterized by insulin ceptor. This has in turn attracted resistance and high levels of blood sugar. significant attention from the pharmaceutical industry over the Hyperglycemia: Presence of an last decade (Figure 1) . Five smallabnormally high concentration of molecule GPR119 agonists have glucose in the blood. entered human clinical trials, and Incretin: Insulinotropic a multitude of new patent applicasubstances originating in the GI tions have appeared. As Figure 1 tract that are released into the circulation by meals containing indicates, much of the patent activglucose. ity in this area has occurred in the last few years, reflecting increasing interest in GPR119 in response to reports of clinical proof-of-concept in glycemic control, via this unique dual mechanism [4] . Herein, we describe the recent patent applications related to GPR119 that were published during the 2009–2011 time period. Each section of the review article describes the activity of individual applicants and this work follows on from an extensive earlier review by the authors that describes patent application filings in this field from 2003–2009 [5] . Key terms
Prosidion Ltd
Prosidion has made significant progress in advancing their GPR119 program, with their lead agonist,
PSN-821, successfully advancing into Phase II human trials in May of 2011 [202] . In a related development, the company recently granted AstraZeneca the option to acquire this compound, and its other lead candidate, PSN-842 [203] . Further reflecting Prosidion’s commitment to developing agonists of this receptor, their IP effort has been very productive over the last few years, with 12 new patent applications entering the public domain (Figure 2) . Prosidion’s first application to appear in the 2009–2011 time period describes a series of thiazole derivatives exemplified by 1 [101] . In vitro GPR119 activity was determined using an ALPHAscreen cAMP functional assay and 1 is reported have an EC50 value of
For reprint orders, please contact [email protected]
GPR119 agonists 2009–2011 Daniel J Buzard*, Juerg Lehmann, Sangdon Han & Robert M Jones The increasing incidence of Type II diabetes mellitus worldwide continues to attract the attention and resources of the pharmaceutical industry in the pursuit of more effective therapies for blood glucose control. New approaches that compare favorably with classical medicaments while avoiding hypoglycemic episodes or waning effectiveness are paramount. Recent advances toward this end have been realized based on the biology of the glucagon like peptide-1 receptor (GLP1R). This b-cell-expressed GPCR has the ability to promote insulin release in a glucose-dependent fashion, and has been shown to elicit improved glycemic control and preservation of b-cell mass. Direct activation of GLP1R utilizing peptide mimetics has been achieved; however, attempts to access the biology of this receptor via small-molecule approaches have thus far been elusive. In this context, GPR119 has emerged as a tractable new alternative to GLP1R. GPR119 is another GPCR expressed on the b-cell, which, like GLP1R, signals in a glucose-dependent manner. Moreover, GPR119-mediated increases in GLP-1 and other incretins upon activation in the intestine further increase the insulinotropic activity of the b-cell. The early success in identifying small-molecule agonists of the GPR119 has prompted a rapid increase in the number of patent applications filed in the last few years. In this review we provide a comprehensive summary of all patent activity in this field that has appeared within the 2009–2011 timeframe. Type II diabetes mellitus remains a global epidemic; in the USA alone, 25.8 million
individuals have been diagnosed with the disease [201] . Worldwide, this number exceeds 171 million and is projected to double over the next several decades [1] . Uncontrolled hyperglycemia in these individuals results in complications such as heart disease and stroke, blindness, kidney disease, nervous system disease and increased mortality. Lifestyle modification can delay the onset and severity of Type II diabetes, but pharmacological intervention is frequently required to manage hyperglycemia uncontrolled by diet or exercise. The development of new therapeutics targeting the b-cell-expressed glucagonlike peptide-1 receptor (GLP1R) has greatly increased the options available to patients and physicians [2] . Activation of this GPCR leads to an increase in insulin output in response to rising glucose levels, and therefore an improvement in glycemic control. This outcome has been exploited by the development of dipeptidyl peptidase-4 (DPP-IV) inhibitors, which block GLP-1 degradation (e.g., Januvia®). GLP-1 mimetics, or glutides, such as Byetta®, have also been successful in helping patients achieve glucose control, although these approaches have required injectable peptide formulations due to the difficulty thus far in identifying orally bioavailable small-molecule GLP1R agonists. GPR119 is another GPCR expressed on the b-cell that, when activated, stimulates insulin release in response to rising levels of glucose via a Gas-mediated increase in cAMP [3] . In addition to GPR119 signaling on the b-cell, these agonists also elevate GLP-1, GIP and PYY levels through activation of GPR119 expressed on intestinal enteroendocrine cells. Elevated levels of these incretins, in turn, activate their cognate receptors on the b-cell and elsewhere, affording additional insulin secretion. Thus, the biology of GPR119 entails two complementary mechanisms for glucose control.
10.4155/PPA.12.33 © 2012 Future Science Ltd
Pharm. Pat. Analyst (2012) 1(3), 285–299
Department of Medicinal Chemistry, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA, *Author for correspondence: Tel.: +1 858 453 7200 E-mail: [email protected]
ISSN 2046-8954
285
Patent Review
Buzard, Lehmann, Han & Jones
Compared to GLP1R, GPR119 has been much more amenable to Type II diabtes mellitus: Adultsmall-molecule approaches aimed onset or non-insulin-dependent at accessing the biology of this rediabetes. Characterized by insulin ceptor. This has in turn attracted resistance and high levels of blood sugar. significant attention from the pharmaceutical industry over the Hyperglycemia: Presence of an last decade (Figure 1) . Five smallabnormally high concentration of molecule GPR119 agonists have glucose in the blood. entered human clinical trials, and Incretin: Insulinotropic a multitude of new patent applicasubstances originating in the GI tions have appeared. As Figure 1 tract that are released into the circulation by meals containing indicates, much of the patent activglucose. ity in this area has occurred in the last few years, reflecting increasing interest in GPR119 in response to reports of clinical proof-of-concept in glycemic control, via this unique dual mechanism [4] . Herein, we describe the recent patent applications related to GPR119 that were published during the 2009–2011 time period. Each section of the review article describes the activity of individual applicants and this work follows on from an extensive earlier review by the authors that describes patent application filings in this field from 2003–2009 [5] . Key terms
Prosidion Ltd
Prosidion has made significant progress in advancing their GPR119 program, with their lead agonist,
PSN-821, successfully advancing into Phase II human trials in May of 2011 [202] . In a related development, the company recently granted AstraZeneca the option to acquire this compound, and its other lead candidate, PSN-842 [203] . Further reflecting Prosidion’s commitment to developing agonists of this receptor, their IP effort has been very productive over the last few years, with 12 new patent applications entering the public domain (Figure 2) . Prosidion’s first application to appear in the 2009–2011 time period describes a series of thiazole derivatives exemplified by 1 [101] . In vitro GPR119 activity was determined using an ALPHAscreen cAMP functional assay and 1 is reported have an EC50 value of
