Discovery of 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazoles as novel class of corticotropin releasing factor 1 receptor antagonists

Abstract A new class of corticotropin releasing factor 1 (CRF 1 ) receptor antagonists characterized by a tricyclic core ring was designed and synthesized. Novel tricyclic derivatives 2a – e were designed as CRF 1 receptor antagonists based on conformation analysis of our original 2-anilinobenzimidazole CRF 1 receptor antagonist. The synthesized tricyclic derivatives 2a – e showed CRF 1 receptor binding activity with IC 50 values of less than 400 nM, and the 1,2,3,4-tetrahydropyrimido-[1,2- a ]benzimidazole derivative 2e was selected as a lead compound with potent in vitro CRF 1 receptor binding activity (IC 50  = 7.1 nM). To optimize the pharmacokinetic profiles of lead compound 2e , we explored suitable substituents on the 1-position and 6-position, leading to the identification of compound 42c -R , which exhibited potent CRF 1 receptor binding activity (IC 50  = 58 nM) with good oral bioavailability (F = 68% in rats). Compound 42c -R exhibited dose-dependent inhibition of [ 125 I]-CRF binding in the frontal cortex (5 and 10 mg/kg, p.o.) as well as suppression of locomotor activation induced by intracerebroventricular administration of CRF in rats (10 mg/kg, p.o.). These results suggest that compound 42c -R successfully binds CRF 1 receptors in the brain and exhibits the potential to be further examined for clinical studies.