Heteroatom insertion into 3,4-dihydro-1H-quinolin-2-ones leads to potent and selective inhibitors of human and rat aldosterone synthase

Eur J Med Chem. 2015 Jan 27:90:788-96. doi: 10.1016/j.ejmech.2014.12.022. Epub 2014 Dec 13.

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).

Keywords: 11β-hydroxylase; Aldosterone; Aldosterone synthase; Cardiovascular diseases; Rat CYP11B2; Selectivity.

MeSH terms

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

Substances

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