Bioorganic and Medicinal Chemistry p. 1247 - 1254 (1999)
Update date:2022-07-31
Topics:
Ohtake, Yasuhiro
Naito, Akira
Hasegawa, Hisashi
Kawano, Katsuhiro
Morizono, Daisuke
Taniguchi, Makoto
Tanaka, Yoko
Matsukawa, Hidehiko
Naito, Kenji
Oguma, Touru
Ezure, Yohji
Tsuriya, Yoshihiro
The intent of the work was to study the structure-activity relationships of AVP receptor antagonists bearing a chiral ring as a partial structure since such studies had been reported for only achiral compounds. In the present paper, we deal with compounds consisting of the chiral tricyclic hetero ring (1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoxaline and 1,2,3,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine) and 2-phenylbenzanilide analogues. These compounds exhibited a highly selective affinity for V2 receptor, and their stereochemical configuration had a great influence on V2 receptor binding. VP-343 (N-[4-[[(2S,3aR)-2-hydroxy-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinoxalin-5(1H)-yl]carbonyl]phenyl]-4'-methyl[1,1'-biphenyl]-2-carboxamide), VP-365 (N-[4-[[(11aS)-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-10(5H)-yl]carbonyl]phenyl][1,1'-biphenyl]-2-carboxamide) and VP-339 (N-[4-[[(11aS)-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-10(5H)-yl]carbonyl]phenyl][1,1'-biphenyl]-2-carboxamide) were the most potent compounds in vitro and in vivo. The IC50 values of VP-343, VP-365 and VP-339 against V2 receptor were 0.772, 1.18 and 0.216nM, respectively. The ED300 values (dose required to increase three times the urine volume of the control rats; oral administration) of VP-343, VP-365 and VP-339 were 0.22, 0.31 and 0.78mg/kg, respectively. Copyright (C) 1999 Elsevier Science Ltd.
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Doi:10.1007/BF03192411
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