Novel Pyridyl Substituted 4,5-Dihydro-[1,2,4]triazolo[4,3‑<i>a</i>]quinolines as Potent and Selective Aldosterone Synthase Inhibitors with Improved in Vitro Metabolic Stability

Abstract

CYP11B2 inhibition is a promising treatment for diseases caused by excessive aldosterone. To improve the metabolic stability in human liver miscrosomes of previously reported CYP11B2 inhibitors, modifications were performed via a combination of ligand- and structure-based drug design approaches, leading to pyridyl 4,5-dihydro-[1,2,4]­triazolo­[4,3-<i>a</i>]­quinolones. Compound <b>26</b> not only exhibited a much longer half-life (<i>t</i>_1/2 ≫ 120 min), but also sustained inhibitory potency (IC₅₀ = 4.2 nM) and selectivity over CYP11B1 (SF = 422), CYP17, CYP19, and a panel of hepatic CYP enzymes