Discovery of a 7-arylaminobenzimidazole series as novel CRF1 receptor antagonists

Publication date: 1 October 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
Author(s): Michiyo Mochizuki, Masakuni Kori, Mitsunori Kono, Takahiko Yano, Yuu Sako, Maiko Tanaka, Naoyuki Kanzaki, Albert C. Gyorkos, Christopher P. Corrette, Kazuyoshi Aso
A promising lead compound 1 of a benzimidazole series has been identified as a corticotropin-releasing factor 1 (CRF1) receptor antagonist. In this study, we focused on replacement of a 7-alkylamino group of 1, predicted to occupy a large lipophilic pocket of a CRF1 receptor, with an aryl group. During the course of this examination, we established new synthetic approaches to 2,7-diarylaminobenzimidazoles. The novel synthesis of 7-arylaminobenzimidazoles culminated in the identification of compounds exhibiting inhibitory activities comparable to the alkyl analog 1. A representative compound, p-methoxyanilino analog 16g, showed potent CRF binding inhibitory activity against a human CRF1 receptor and human CRF1 receptor antagonistic activity (IC50=27nM, 56nM, respectively). This compound exhibited ex vivo ¹²⁵I-Tyr⁰ (¹²⁵I-CRF) binding inhibitory activity in mouse frontal cortex, olfactory bulb, and pituitary gland at 20mg/kg after oral administration. In this report, we discuss the structure–activity-relationship of these 7-arylamino-1H-benzimidazoles and their synthetic method.

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