title: Novel pyridyl- or isoquinolinyl-substituted indolines and indoles as potent and selective aldosterone synthase inhibitors.
abstract: Pathologically, high levels of aldosterone are associated with severe cardiovascular diseases such as congestive heart failure, hypertension, and myocardial fibrosis. The inhibition of aldosterone synthase (CYP11B2) to reduce aldosterone levels has been proposed as a promising treatment for diseases related to CYP11B2 because it is the crucial enzyme in the biosynthesis of aldosterone. A series of novel pyridyl- or isoquinolinyl-substituted indolines and indoles was designed via a ligand-based approach. The synthesized compounds were tested and found to be strong CYP11B2 inhibitors. The most potent ones showed IC50 values of less than 3 nM, being similarly potent as fadrozole and LCI699. Among them, compounds 14 and 23 showed good selectivity over the highly homologous CYP11B1, with selectivity factors (SF = IC50 CYP11B1/IC50 CYP11B2) around 170; thus, they are superior to fadrozole and LCI699 (SFs < 15). These potent CYP11B2 inhibitors exhibited no inhibition (IC50 > 50 μM) of a panel of hepatic CYP enzymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 and the crucial steroidogenic enzymes, CYP17 and CYP19. Because of these advantageous profiles, compounds 14 and 23 are considered to be candidates for further in vivo evaluation.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University , Campus C2.3, D-66123 Saarbrücken, Germany.
authors.forename: Lina
authors.initials: L
authors.lastname: Yin
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Hu
authors.forename: Juliette
authors.initials: J
authors.lastname: Emmerich
authors.forename: Michael Man-Chu
authors.initials: MM
authors.lastname: Lo
authors.forename: Edward
authors.initials: E
authors.lastname: Metzger
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D000818:Animals; D001141:Aromatase / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008099:Liver / Q000201:enzymology; D062105:Molecular Docking Simulation; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: C000591343:1-acetyl-5-(4-methylpyridin-3-yl)-2,3-dihydro-1H-indole; C000591342:4-(1-propanoyl-2,3-dihydro-1H-indol-5-yl)isoquinoline; D007211:Indoles; D007546:Isoquinolines; D011725:Pyridines; D001141:Aromatase; D013254:Steroid 17-alpha-Hydroxylase; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase