Discovery of 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole, a novel CRF1 receptor antagonist

Abstract Compound 1 exhibits potent binding inhibition activity against a corticotropin-releasing factor 1 (CRF 1 ) receptor (IC 50  = 9.5 nM) and in vitro antagonistic activity (IC 50  = 88 nM) but is rapidly metabolized by human hepatic microsomes (182 μL/min/mg). Here we identified metabolically stable compounds with potent CRF binding inhibitory activity. Structure–activity relationship (SAR) studies considering in vitro metabolic stability revealed that 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1 H -benzimidazole 24d was more stable in human microsomes (87 μL/min/mg) than compound 1 . Compound 24d demonstrated potent CRF binding inhibitory activity (IC 50  = 4.1 nM), in vitro antagonistic activity (IC 50  = 44 nM), and slow dissociation from the CRF 1 receptor. Orally administered compound 24d (6–24 μmol/kg) showed ex vivo CRF 1 receptor binding in the rat pituitary, olfactory bulb, and frontal cortex and suppressed stress-induced adrenocorticotropic hormone (ACTH) secretion. In this report, we discuss SAR studies on the metabolic stability as well as CRF binding inhibitory activity of the benzimidazole series as CRF 1 receptor antagonists and the pharmacological profiles of compound 24d .