title: Heteroatom insertion into 3,4-dihydro-1H-quinolin-2-ones leads to potent and selective inhibitors of human and rat aldosterone synthase.
abstract: Aldosterone synthase (CYP11B2) catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone. CYP11B2 is regarded as a new target for several cardiovascular diseases which are associated with chronically elevated aldosterone levels such as hypertension, congestive heart failure and myocardial fibrosis. In this paper, we optimized heterocycle substituted 3,4-dihydropyridin-2(1H)-ones as CYP11B inhibitors by systematic introduction of heteroatoms and by bioisosteric exchange of the lactame moiety by a sultame moiety. The most promising compounds regarding inhibition of human CYP11B2 and selectivity versus human enzymes CYP11B1, CYP17, and CYP19 were tested for inhibition of rat CYP11B2. Thus, we discovered compounds 4 and 9 which show potent inhibition of hCYP11B2 (IC50 < 1 nM) and the corresponding rat enzyme (4: 64%, 9: 51% inhibition, at 2 μM).
authors.affiliation: Pharmaceutical and Medicinal Chemistry, 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, Campus C2 3, D-66123 Saarbrücken, Germany.
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Pharmaceutical and Medicinal Chemistry, 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, Campus C2 3, D-66123 Saarbrücken, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Zimmer
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2 3, D-66123 Saarbrücken, Germany; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), 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; D002460:Cell Line; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D015363:Quinolones; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase
keywords: 11β-hydroxylase; Aldosterone; Aldosterone synthase; Cardiovascular diseases; Rat CYP11B2; Selectivity