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: Cornelia M Grombein, Qingzhong Hu, Sabrina Rau, Christina Zimmer, Rolf W Hartmann
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 90 Pg. 788-96 (Jan 27 2015) ISSN: 1768-3254 [Electronic] France
• PMID: 25528333 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Quinolones
• Cytochrome P-450 CYP11B2
• Steroid 11-beta-Hydroxylase

Topics

• Animals
• Cell Line
• Cytochrome P-450 CYP11B2 (antagonists & inhibitors, metabolism)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Molecular Structure
• Quinolones (chemical synthesis, chemistry, pharmacology)
• Rats
• Steroid 11-beta-Hydroxylase (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship