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

Publication date: Available online 8 November 2016
Source:Bioorganic & Medicinal Chemistry
Author(s): Michiyo Mochizuki, Takuto Kojima, Katsumi Kobayashi, Etsuo Kotani, Yuji Ishichi, Naoyuki Kanzaki, Hideyuki Nakagawa, Teruaki Okuda, Yohei Kosugi, Takahiko Yano, Yuu Sako, Maiko Tanaka, Kazuyoshi Aso
Compound 1 exhibits potent binding inhibition activity against a corticotropin-releasing factor 1 (CRF1) receptor (IC50 = 9.5 nM) and in vitro antagonistic activity (IC50 = 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)-1H-benzimidazole 24d was more stable in human microsomes (87 μL/min/mg) than compound 1. Compound 24d demonstrated potent CRF binding inhibitory activity (IC50 = 4.1 nM), in vitro antagonistic activity (IC50 = 44 nM), and slow dissociation from the CRF1 receptor. Orally administered compound 24d (6–24 μmol/kg) showed ex vivo CRF1 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 CRF1 receptor antagonists and the pharmacological profiles of compound 24d.

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