Novel 5-hydroxytryptamine (5-HT3) receptor antagonists. I. Synthesis and structure-activity relationships of conformationally restricted fused imidazole derivatives.
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 microgram/kg on the von Bezold-Jarisch reflex in rats and an IC50 value of 0.43 microM 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-methoxyphenyl)aminocarbonyl part in the binding of 14 to the receptor.
Ohta
M
M
Neuroscience/Gastrointestinal Research Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Suzuki
T
T
Koide
T
T
Matsuhisa
A
A
Furuya
T
T
Miyata
K
K
Yanagisawa
I
I
D000818:Animals; D003106:Colon / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D007093:Imidazoles / Q000737:chemistry; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects*; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D007093:Imidazoles; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists