Discovery of indazole aldosterone synthase (CYP11B2) inhibitors as potential treatments for hypertension

Bioorg Med Chem Lett. 2017 Jun 1;27(11):2384-2388. doi: 10.1016/j.bmcl.2017.04.021. Epub 2017 Apr 8.

Abstract

We report the discovery and hit-to-lead optimization of a structurally novel indazole series of CYP11B2 inhibitors. Benchmark compound 34 from this series displays potent inhibition of CYP11B2, high selectivity versus related steroidal and hepatic CYP targets, and lead-like physical and pharmacokinetic properties. On the basis of these and other data, the indazole series was progressed to lead optimization for further refinement.

Keywords: Aldosterone synthase; CYP11B2; Hit-to-lead; Hypertension; Indazole.

MeSH terms

  • Animals
  • Antihypertensive Agents / chemical synthesis
  • Antihypertensive Agents / pharmacokinetics
  • Antihypertensive Agents / pharmacology*
  • Aromatase Inhibitors / chemical synthesis
  • Aromatase Inhibitors / pharmacokinetics
  • Aromatase Inhibitors / pharmacology
  • Cell Line
  • Cricetulus
  • Cytochrome P-450 CYP11B2 / antagonists & inhibitors*
  • Cytochrome P-450 CYP2D6 Inhibitors / chemical synthesis
  • Cytochrome P-450 CYP2D6 Inhibitors / pharmacokinetics
  • Cytochrome P-450 CYP2D6 Inhibitors / pharmacology
  • Humans
  • Hypertension / drug therapy*
  • Indazoles / chemical synthesis
  • Indazoles / pharmacokinetics
  • Indazoles / pharmacology*
  • Macaca mulatta
  • Male
  • Rats, Sprague-Dawley
  • Stereoisomerism
  • Steroid 11-beta-Hydroxylase / antagonists & inhibitors

Substances

  • 1,1,1-trifluoro-2-(5-(4-(trifluoromethyl)-1H-indazol-1-yl)pyridin-3-yl)propan-2-ol
  • Antihypertensive Agents
  • Aromatase Inhibitors
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Indazoles
  • Cytochrome P-450 CYP11B2
  • Steroid 11-beta-Hydroxylase