title: Novel pyridyl substituted 4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolines as potent and selective aldosterone synthase inhibitors with improved in vitro metabolic stability.
abstract: CYP11B2 inhibition is a promising treatment for diseases caused by excessive aldosterone. To improve the metabolic stability in human liver miscrosomes of previously reported CYP11B2 inhibitors, modifications were performed via a combination of ligand- and structure-based drug design approaches, leading to pyridyl 4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolones. Compound 26 not only exhibited a much longer half-life (t1/2 ≫ 120 min), but also sustained inhibitory potency (IC50 = 4.2 nM) and selectivity over CYP11B1 (SF = 422), CYP17, CYP19, and a panel of hepatic CYP enzymes.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Campus C2-3, D-66123, Saarbrücken, Germany.
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Hu
authors.forename: Lina
authors.initials: L
authors.lastname: Yin
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Cooke
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bennett
authors.forename: Paul
authors.initials: P
authors.lastname: Ratcliffe
authors.forename: Michael Man-Chu
authors.initials: MM
authors.lastname: Lo
authors.forename: Edward
authors.initials: E
authors.lastname: Metzger
authors.forename: Scott
authors.initials: S
authors.lastname: Hoyt
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D001141:Aromatase / Q000737:chemistry* / Q000378:metabolism; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000187:drug effects*; D008958:Models, Molecular; D015394:Molecular Structure; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C000598577:9-fluoro-1-methyl-7-(4-methylpyridin-3-yl)-4,5-dihydro(1,2,4)triazolo(4,3-a)quinoline; D004791:Enzyme Inhibitors; D011804:Quinolines; D014230:Triazoles; D000450:Aldosterone; D001141:Aromatase; D013254:Steroid 17-alpha-Hydroxylase; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase