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

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 = 27 nM, 56 nM, respectively). This compound exhibited ex vivo ¹²⁵I-Tyr⁰ (¹²⁵I-CRF) binding inhibitory activity in mouse frontal cortex, olfactory bulb, and pituitary gland at 20 mg/kg after oral administration. In this report, we discuss the structure–activity-relationship of these 7-arylamino-1H-benzimidazoles and their synthetic method.