1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols: a new class of potent and selective aldosterone synthase inhibitors

Eur J Med Chem. 2015 Jan 7:89:597-605. doi: 10.1016/j.ejmech.2014.10.027. Epub 2014 Oct 12.

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.

Keywords: 1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols; 11β-hydroxylase; Aldosterone; Aldosterone synthase; Selectivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytochrome P-450 CYP11B2 / antagonists & inhibitors*
  • Cytochrome P-450 CYP11B2 / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / classification*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Male
  • Models, Molecular
  • Naphthols / chemical synthesis
  • Naphthols / chemistry
  • Naphthols / pharmacology*
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship
  • Sulfoxides / chemical synthesis
  • Sulfoxides / chemistry
  • Sulfoxides / pharmacology*

Substances

  • Enzyme Inhibitors
  • Naphthols
  • Sulfoxides
  • Cytochrome P-450 CYP11B2