title: 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.
abstract: 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. This property of LCI699 prompted its development in Cushing's disease, but limited more extensive clinical studies in hypertensive populations, and provided an impetus for the search for cortisol-sparing CYP11B2 inhibitors. This paper summarizes the discovery, pharmacokinetics, and pharmacodynamic data in preclinical species and human subjects of the selective CYP11B2 inhibitor 8.
authors.forename: Julien P N
authors.initials: JP
authors.lastname: Papillon
authors.forename: Changgang
authors.initials: C
authors.lastname: Lou
authors.forename: Alok K
authors.initials: AK
authors.lastname: Singh
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Adams
authors.forename: Gary M
authors.initials: GM
authors.lastname: Ksander
authors.affiliation: Cardiovascular and Metabolism, Novartis Institutes for BioMedical Research , One Health Plaza, East Hanover, New Jersey 07936, United States.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Beil
authors.affiliation: Cardiovascular and Metabolism, Novartis Institutes for BioMedical Research , One Health Plaza, East Hanover, New Jersey 07936, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Cardiovascular and Metabolism, Novartis Institutes for BioMedical Research , One Health Plaza, East Hanover, New Jersey 07936, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Leung-Chu
authors.affiliation: Cardiovascular and Metabolism, Novartis Institutes for BioMedical Research , One Health Plaza, East Hanover, New Jersey 07936, United States.
authors.forename: Fumin
authors.initials: F
authors.lastname: Fu
authors.forename: Lu
authors.initials: L
authors.lastname: Gan
authors.affiliation: Cardiovascular and Metabolism, Novartis Institutes for BioMedical Research , One Health Plaza, East Hanover, New Jersey 07936, United States.
authors.forename: Chii-Whei
authors.initials: CW
authors.lastname: Hu
authors.affiliation: Cardiovascular and Metabolism, Novartis Institutes for BioMedical Research , One Health Plaza, East Hanover, New Jersey 07936, United States.
authors.forename: Arco Y
authors.initials: AY
authors.lastname: Jeng
authors.affiliation: Cardiovascular and Metabolism, Novartis Institutes for BioMedical Research , One Health Plaza, East Hanover, New Jersey 07936, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: LaSala
authors.forename: Guiqing
authors.initials: G
authors.lastname: Liang
authors.affiliation: Cardiovascular and Metabolism, Novartis Institutes for BioMedical Research , One Health Plaza, East Hanover, New Jersey 07936, United States.
authors.forename: Dean F
authors.initials: DF
authors.lastname: Rigel
authors.forename: Kerry S
authors.initials: KS
authors.lastname: Russell
authors.forename: John A
authors.initials: JA
authors.lastname: Vest
authors.forename: Catherine
authors.initials: C
authors.lastname: Watson
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D054879:Halogenation; D000882:Haplorhini; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D008745:Methylation; D000451:Mineralocorticoid Receptor Antagonists / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D000451:Mineralocorticoid Receptor Antagonists; D011725:Pyridines; D013449:Sulfonamides; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2