title: 1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols: a new class of potent and selective aldosterone synthase inhibitors.
abstract: 1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols and related compounds were synthesized and evaluated for inhibition of aldosterone synthase (CYP11B2), a potential target for cardiovascular diseases associated with elevated plasma aldosterone levels like congestive heart failure and myocardial fibrosis. Introduction of substituents at the phenylsulfinyl moiety and changes of the substitution pattern at the naphthalene core were examined. Potent compounds were further examined for selectivity versus other important steroidogenic CYP enzymes, i.e. the highly homologous 11β-hydroxylase (CYP11B1), CYP17 and CYP19. The most potent compound (IC50 = 14 nM) discovered was the meta-trifluoromethoxy derivative 11, which also exhibited excellent selectivity toward CYP11B1 (SF = 415), and showed no inhibition of CYP17 and CYP19.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarland University, Campus C2(3), D-66123 Saarbrücken, Germany.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Grombein
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarland University, Campus C2(3), D-66123 Saarbrücken, Germany.
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarland University, Campus C2(3), D-66123 Saarbrücken, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Heim
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarland University, Campus C2(3), D-66123 Saarbrücken, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Rau
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarland University, Campus C2(3), D-66123 Saarbrücken, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Zimmer
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarland University, Campus C2(3), D-66123 Saarbrücken, Germany. Electronic address: rolf.hartmann@helmholtz-hzi.de.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D000818:Animals; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000145:classification* / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009284:Naphthols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013454:Sulfoxides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D009284:Naphthols; D013454:Sulfoxides; D019405:Cytochrome P-450 CYP11B2
keywords: 1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols; 11β-hydroxylase; Aldosterone; Aldosterone synthase; Selectivity