Abstract
We prepared a novel series of conformationally restricted fused imidazole derivatives 4b, 4c and 4d (possessing 4, 5, 6, 7-tetrahydroimidazo[4, 5-c]pyridine and substituted 4, 5, 6, 7-tetrahydro-1H-benzimidazole for 4b, 5, 6, 7, 8-tetrahydroimidazo[1, 2-a]pyridine for 4c and 5, 6, 7, 8-tetrahydroimidazo[1, 5-a]pyridine for 4d as a basic amine part and (2-methoxyphenyl)aminocarbonyl group as an aromatic-carbonyl part). Their activities were then evaluated as an 5-hydroxytryptamine (5-HT3) receptor antagonist which may be useful for the treatment of irritable bowel syndrome (IBS) as well as for nausea and vomiting associated with cancer chemotherapy. The most potent compound was N-(2-methoxyphenyl)-4, 5, 6, 7-tetrahydro-1H-benzimidazole-5-carboxamide 14 in this series with an ID50 value of 0.32 μg/kg on the von Benzold-Jarisch reflex in rats and an IC50 value of 0.43 μM on the isolated colonic contraction in guinea pig, approximately ten and two times more potent than ondansetron 1, respectively. The structure-activity relationships (SAR) study suggested that the high potency of 14 may be attributed to the suitable position and direction of the N-C-N centroid in the conformationally restricted imidazole ring against the planar (2-methoxy-phenyl)aminocarbonyl part in the binding of 14 to the receptor.
