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Discovery Heralds New Approach to the Treatment of Cystic Fibrosis John A. Lowe, III* JL3Pharma LLC, 28 Cove Side Lane, Stonington, Connecticut 06378, United States ystic fibrosis (CF) is a lethal obstructive airways disease that afflicts more than 80 000 patients worldwide.1 The cause of CF was elucidated in 1989 by the cloning of the gene for the CF transmembrane conductance regulator (CFTR), which controls chloride and bicarbonate transport across epithelial membranes in multiple organs such as the lung and GI tract. There are over 1900 known mutations in the CFTR gene, which compromise its function and lead to a buildup of mucus, airway obstruction, and the growth of pathogenic bacteria.2 In this issue, a team from Vertex reports the discovery of the first small molecule potentiator for one of the mutant CFTRs, heralding a new era in the treatment of CF.3 When CF was first comprehensively described as a disease in the late 1930s, life expectancy was only a year or two for CF patients.4 The introduction of antibiotics following World War II, and especially Gram negative antibiotics in the 1960s, saw this increase into the teens (Figure 1). When the CF gene was
C
function, specifically the open probability (Po). By use of this assay, an HTS screening campaign detected a promising hit, compound 1.
The Vertex team first determined that the quinolone ring is strictly conserved and that replacement of the amide with an anilide further improves activity. One anilide in particular, the 6-indolyl group, seemed especially promising. They hypothesized that the indole N−H makes a favorable interaction in the mutant CFTR protein in order to improve its function. Despite its druglike properties, e.g., a cLogP of 1.6, compound 2 showed low solubility and high clearance in the rat, leading to low oral bioavailability. To remedy this, substitution on the indole and ring-opening were examined, showing that a 3-tertbutyl substituent and ring-opening to the bioisosteric phenol improve activity. Addition of a second tert-butyl group to the phenol ring led to compound 3. Compound 3 shows improved rat pharmacokinetics, with a 9.5 h half-life and 55% oral bioavailability. It has improved solubility and no significant off-target activity or P450 inhibition. It was examined for its ability to increase gating in the F508del/G551D CFTR mutant from human bronchial epithelium (HBE), which contains a folding defect (F508del) and a gating defect (G551D). It shows an EC50 value of 0.236 μM, with chloride secretion reaching 50% of the level seen in non-CF HBE. These results suggest the potential for compound 3 to potentiate the function of multiple mutant forms of CFTR. Given its favorable projected human pharmacokinetics, compound 3 was advanced to clinical development. It was subsequently approved in 2012 for the treatment of CF patients over 5 years old with the G551D gating mutation and is currently marketed as Kalydeco.
Figure 1. Changes in life expectancy for CF patients from 1950 to 2010. Data obtained from ref 4.
first identified in 1989, this had further increased to 25 years. With understanding of the etiology of CF and better mucusthinning agents and antibiotics, CF life expectancy has reached over 40 years today. Vertex’s discovery of a small molecule to correct the deficient function of one of the CFTR mutants is the first drug to go beyond these symptomatic treatments. Mutant CFTR deficiency falls into two categories: folding mutants that cause the channel to fail to transport to the cell surface resulting in degradation, and mutants that reach the cell surface but fail to conduct anions.5 Finding a small molecule to “correct” a deficient protein may seem outside the realm of feasible drug discovery with small molecules. But the group at Vertex tackled this problem using phenotypic screening, a technique that has seen a recent resurgence in popularity.6 Their assay was designed to detect compounds to correct either type of CFTR deficiency: correctors to help translocate the protein to the cell surface, and potentiators to increase its © XXXX American Chemical Society
Received: October 31, 2014
A
dx.doi.org/10.1021/jm5016928 | J. Med. Chem. XXXX, XXX, XXX−XXX
Journal of Medicinal Chemistry
Viewpoint
Vertex’s willingness to gamble on such a risky therapeutic approach, a small molecule to correct a deficient protein, deserves a great deal of credit. The crucial research support for this project from the Cystic Fibrosis Foundation is a tribute to the power of patient advocacy foundations in finding a cure for orphan diseases.7 Vertex has reported more advances in CF correctors, with multiple agents now in clinical trials, some in combination with Kalydeco.8,9 Hopefully the life expectancy curve for CF patients will continue its upward journey from the dark days of 1950 until it promises CF patients a full and healthy life.
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AUTHOR INFORMATION
Corresponding Author
*Phone: 860-535-4283. E-mail: [email protected].
REFERENCES
(1) Cohen-Cymberknoh, M.; Shoseyov, D.; Kerem, E. Managing cystic fibrosis: strategies that increase life expectancy and improve quality of life. Am. J. Respir. Crit. Care Med. 2011, 183, 1463−1471. (2) Welsh, M. J.; Smith, A. E. Molecular mechansims of CFTR chloride channel dysfunction in cystic fibrosis. Cell 1993, 73, 1251− 1254. (3) Hadida, S.; Van Goor, F.; Zhou, J.; Arumugam, V.; McCartney, J.; Hazelwood, A.; Decker, C.; Negulescu, P.; Grootenhuis, P. D. J. Discovery of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, ivacaftor), a potent and orally bioavailable CFTR potentiator. J. Med. Chem. 2014, DOI: 10.1021/ jm5012808. (4) National Jewish Health. Cystic Fibrosis: Life Expectancy. http:// www.nationaljewish.org/healthinfo/conditions/cysticfibrosis/lifeexpectancy/. (5) Patrick, A. E.; Thomas, P. J. Development of CFTR structure. Front. Pharmacol. 2012, 3, 6−16. (6) Prior, M.; Chiruta, C.; Currais, A.; Goldberg, J.; Ramsey, J.; Dargusch, R.; Maher, P. A.; Schubert, D. Back to the future with phenotypic screening. ACS Chem. Neurosci. 2014, 5, 503−513. (7) Cystic Fibrosis Foundation. www.cff.org. (8) Clancy, J. P.; Rowe, S. M.; Accurso, F. J.; et al. Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation. Thorax 2012, 67, 12−18. (9) Hanrahan, J. W.; Sampson, H. M.; Thomas, D. Y. Novel pharmacological strategies to treat cystic fibrosis. Trends Pharmacol. Sci. 2013, 34, 119−125.
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dx.doi.org/10.1021/jm5016928 | J. Med. Chem. XXXX, XXX, XXX−XXX
Discovery Heralds New Approach to the Treatment of Cystic Fibrosis John A. Lowe, III* JL3Pharma LLC, 28 Cove Side Lane, Stonington, Connecticut 06378, United States ystic fibrosis (CF) is a lethal obstructive airways disease that afflicts more than 80 000 patients worldwide.1 The cause of CF was elucidated in 1989 by the cloning of the gene for the CF transmembrane conductance regulator (CFTR), which controls chloride and bicarbonate transport across epithelial membranes in multiple organs such as the lung and GI tract. There are over 1900 known mutations in the CFTR gene, which compromise its function and lead to a buildup of mucus, airway obstruction, and the growth of pathogenic bacteria.2 In this issue, a team from Vertex reports the discovery of the first small molecule potentiator for one of the mutant CFTRs, heralding a new era in the treatment of CF.3 When CF was first comprehensively described as a disease in the late 1930s, life expectancy was only a year or two for CF patients.4 The introduction of antibiotics following World War II, and especially Gram negative antibiotics in the 1960s, saw this increase into the teens (Figure 1). When the CF gene was
C
function, specifically the open probability (Po). By use of this assay, an HTS screening campaign detected a promising hit, compound 1.
The Vertex team first determined that the quinolone ring is strictly conserved and that replacement of the amide with an anilide further improves activity. One anilide in particular, the 6-indolyl group, seemed especially promising. They hypothesized that the indole N−H makes a favorable interaction in the mutant CFTR protein in order to improve its function. Despite its druglike properties, e.g., a cLogP of 1.6, compound 2 showed low solubility and high clearance in the rat, leading to low oral bioavailability. To remedy this, substitution on the indole and ring-opening were examined, showing that a 3-tertbutyl substituent and ring-opening to the bioisosteric phenol improve activity. Addition of a second tert-butyl group to the phenol ring led to compound 3. Compound 3 shows improved rat pharmacokinetics, with a 9.5 h half-life and 55% oral bioavailability. It has improved solubility and no significant off-target activity or P450 inhibition. It was examined for its ability to increase gating in the F508del/G551D CFTR mutant from human bronchial epithelium (HBE), which contains a folding defect (F508del) and a gating defect (G551D). It shows an EC50 value of 0.236 μM, with chloride secretion reaching 50% of the level seen in non-CF HBE. These results suggest the potential for compound 3 to potentiate the function of multiple mutant forms of CFTR. Given its favorable projected human pharmacokinetics, compound 3 was advanced to clinical development. It was subsequently approved in 2012 for the treatment of CF patients over 5 years old with the G551D gating mutation and is currently marketed as Kalydeco.
Figure 1. Changes in life expectancy for CF patients from 1950 to 2010. Data obtained from ref 4.
first identified in 1989, this had further increased to 25 years. With understanding of the etiology of CF and better mucusthinning agents and antibiotics, CF life expectancy has reached over 40 years today. Vertex’s discovery of a small molecule to correct the deficient function of one of the CFTR mutants is the first drug to go beyond these symptomatic treatments. Mutant CFTR deficiency falls into two categories: folding mutants that cause the channel to fail to transport to the cell surface resulting in degradation, and mutants that reach the cell surface but fail to conduct anions.5 Finding a small molecule to “correct” a deficient protein may seem outside the realm of feasible drug discovery with small molecules. But the group at Vertex tackled this problem using phenotypic screening, a technique that has seen a recent resurgence in popularity.6 Their assay was designed to detect compounds to correct either type of CFTR deficiency: correctors to help translocate the protein to the cell surface, and potentiators to increase its © XXXX American Chemical Society
Received: October 31, 2014
A
dx.doi.org/10.1021/jm5016928 | J. Med. Chem. XXXX, XXX, XXX−XXX
Journal of Medicinal Chemistry
Viewpoint
Vertex’s willingness to gamble on such a risky therapeutic approach, a small molecule to correct a deficient protein, deserves a great deal of credit. The crucial research support for this project from the Cystic Fibrosis Foundation is a tribute to the power of patient advocacy foundations in finding a cure for orphan diseases.7 Vertex has reported more advances in CF correctors, with multiple agents now in clinical trials, some in combination with Kalydeco.8,9 Hopefully the life expectancy curve for CF patients will continue its upward journey from the dark days of 1950 until it promises CF patients a full and healthy life.
■ ■
AUTHOR INFORMATION
Corresponding Author
*Phone: 860-535-4283. E-mail: [email protected].
REFERENCES
(1) Cohen-Cymberknoh, M.; Shoseyov, D.; Kerem, E. Managing cystic fibrosis: strategies that increase life expectancy and improve quality of life. Am. J. Respir. Crit. Care Med. 2011, 183, 1463−1471. (2) Welsh, M. J.; Smith, A. E. Molecular mechansims of CFTR chloride channel dysfunction in cystic fibrosis. Cell 1993, 73, 1251− 1254. (3) Hadida, S.; Van Goor, F.; Zhou, J.; Arumugam, V.; McCartney, J.; Hazelwood, A.; Decker, C.; Negulescu, P.; Grootenhuis, P. D. J. Discovery of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, ivacaftor), a potent and orally bioavailable CFTR potentiator. J. Med. Chem. 2014, DOI: 10.1021/ jm5012808. (4) National Jewish Health. Cystic Fibrosis: Life Expectancy. http:// www.nationaljewish.org/healthinfo/conditions/cysticfibrosis/lifeexpectancy/. (5) Patrick, A. E.; Thomas, P. J. Development of CFTR structure. Front. Pharmacol. 2012, 3, 6−16. (6) Prior, M.; Chiruta, C.; Currais, A.; Goldberg, J.; Ramsey, J.; Dargusch, R.; Maher, P. A.; Schubert, D. Back to the future with phenotypic screening. ACS Chem. Neurosci. 2014, 5, 503−513. (7) Cystic Fibrosis Foundation. www.cff.org. (8) Clancy, J. P.; Rowe, S. M.; Accurso, F. J.; et al. Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation. Thorax 2012, 67, 12−18. (9) Hanrahan, J. W.; Sampson, H. M.; Thomas, D. Y. Novel pharmacological strategies to treat cystic fibrosis. Trends Pharmacol. Sci. 2013, 34, 119−125.
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dx.doi.org/10.1021/jm5016928 | J. Med. Chem. XXXX, XXX, XXX−XXX
