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-N2-(4-chloro-2-methoxy-6-methylphenyl)-1-methyl-N7,N7-dipropyl-1H-benzimidazole-2,7-diamine 29g 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 29g after oral administration in mice. Thus, the newly designed
benzimidazole 29g 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.