Discovery of N‑[5-(6-Chloro-3-cyano-1-methyl‑1H‑indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide, a Cortisol-Sparing CYP11B2 Inhibitor that Lowers Aldosterone in Human Subjects

• Published in: Journal of medicinal chemistry Vol. 58; no. 23; pp. 9382 - 9394
• Main Authors: Papillon, Julien P. N, Lou, Changgang, Singh, Alok K, Adams, Christopher M, Ksander, Gary M, Beil, Michael E, Chen, Wei, Leung-Chu, Jennifer, Fu, Fumin, Gan, Lu, Hu, Chii-Whei, Jeng, Arco Y, LaSala, Daniel, Liang, Guiqing, Rigel, Dean F, Russell, Kerry S, Vest, John A, Watson, Catherine
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.12.2015; Amer Chemical Soc
• Subjects: Aldosterone - metabolism; Animals; Chemistry, Medicinal; Cytochrome P-450 CYP11B2 - antagonists & inhibitors; Cytochrome P-450 CYP11B2 - metabolism; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Halogenation; Haplorhini; Humans; Hypertension - drug therapy; Indoles - chemistry; Indoles - pharmacokinetics; Indoles - pharmacology; Life Sciences & Biomedicine; Methylation; Mineralocorticoid Receptor Antagonists - chemistry; Mineralocorticoid Receptor Antagonists - pharmacokinetics; Mineralocorticoid Receptor Antagonists - pharmacology; Pharmacology & Pharmacy; Pyridines - chemistry; Pyridines - pharmacokinetics; Pyridines - pharmacology; Rats; Rats, Sprague-Dawley; Science & Technology; Sulfonamides - chemistry; Sulfonamides - pharmacokinetics; Sulfonamides - pharmacology; IN-VIVO ACTIVITY; 11-BETA-HYDROXYLASE INHIBITOR; POTENT; SYNTHASE INHIBITION; RESISTANT HYPERTENSION; HEART-FAILURE; SELECTIVE INHIBITORS; DOUBLE-BLIND; CARDIAC FIBROSIS; ANGIOTENSIN

Human clinical studies conducted with LCI699 established aldosterone synthase (CYP11B2) inhibition as a promising novel mechanism to lower arterial blood pressure. However, LCI699’s low CYP11B1/CYP11B2 selectivity resulted in blunting of adrenocorticotropic hormone-stimulated cortisol secretion. Thi...