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J Med Chem. 2015 Mar 12;58(5):2530-7. doi: 10.1021/acs.jmedchem.5b00079. Epub 2015 Mar 3.

Novel pyridyl substituted 4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolines as potent and selective aldosterone synthase inhibitors with improved in vitro metabolic stability.

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Pharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Campus C2-3, D-66123, Saarbrücken, Germany.


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-a]quinolones. Compound 26 not only exhibited a much longer half-life (t1/2 ≫ 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.

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