Novel Imidazol-1-ylmethyl Substituted 1,2,5,6-Tetrahydropyrrolo[3,2,1-<i>ij</i>]quinolin-4-ones as Potent and Selective CYP11B1 Inhibitors for the Treatment of Cushing’s Syndrome

Abstract

CYP11B1 inhibition is a promising therapy for Cushing's syndrome. Starting from etomidate, references I and II, the title compounds were designed and synthesized. Cyclopropyl analogue 4 was identified as a CYP11B1 inhibitor more potent (IC(50) = 2.2 nM) than leads and more selective (SF = 11) than I and metyrapone. Since it also showed potent inhibition of rat CYP11B1 and good selectivity over human CYP17 and CYP19, it is a promising candidate for further development.