Design and Synthesis of Benzimidazoles As Novel Corticotropin-Releasing Factor 1 Receptor Antagonists

Benzazole derivatives with a flexible aryl group bonded through a one-atom linker as a new scaffold for a corticotropin-releasing factor 1 (CRF₁) receptor antagonist were designed, synthesized, and evaluated. We expected that structural diversity could be expanded beyond that of reported CRF₁ receptor antagonists. In a structure–activity relationship study, 4-chloro-<i>N</i>²-(4-chloro-2-methoxy-6-methylphenyl)-1-methyl-<i>N</i>⁷,<i>N</i>⁷-dipropyl-1<i>H</i>-benzimidazole-2,7-diamine <b>29g</b> had the most potent binding activity against a human CRF₁ receptor and the antagonistic activity (IC₅₀ = 9.5 and 88 nM, respectively) without concerns regarding cytotoxicity at 30 μM. Potent CRF₁ receptor-binding activity in brain in an ex vivo test and suppression of stress-induced activation of the hypothalamus–pituitary–adrenocortical (HPA) axis were also observed at 138 μmol/kg of compound <b>29g</b> after oral administration in mice. Thus, the newly designed benzimidazole <b>29g</b> showed in vivo CRF₁ receptor antagonistic activity and good brain penetration, indicating that it is a promising lead for CRF₁ receptor antagonist drug discovery research