Journal of Medicinal Chemistry p. 591 - 609 (1993)
Update date:2022-07-29
Topics:
Ashton
Cantone
Chang
Hutchins
Strelitz
MacCoss
Chang
Lotti
Faust
Chen
Bunting
Schorn
Kivlighn
Siegl
By a variety of synthetic routes, we have synthesized a series of 3,4,5- trisubstituted 4H-1,2,4-triazoles and a related series of 3H-imidazo[1,2- b][1,2,4]triazoles and evaluated them in vitro and in vivo as angiotensin II (AII) antagonists. Principal efforts focused on triazoles bearing an n-alkyl substituent at C3 and a 4-[(2-carboxybenzoyl)amino]benzyl, (2'- carboxybiphenyl-4-yl)methyl, or [2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl side chain at N4. Among numerous variations at C5, benzylthio groups gave the best potency. Particularly noteworthy was 3-n-butyl-5-[(2- carboxybenzyl)thio]-4-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-4H-1,2,4- triazole (71, IC50 1.4 nM), which blocked the AII pressor response in conscious rats at 0.3 mg/kg iv with a duration of action of approximately 6 h, similar to that of DuP 753. Although 71 was active orally only at a 10- fold higher dose level, good oral bioavailability was demonstrated for a monoacidic analogue 62. Most potent among the bicyclic derivatives was 2-n- butyl-5,6-dimethyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-3H- imidazo[1,2-b][1,2,4]triazole (93, IC50 7.8 nM). The effects of hydrophobic, hydrogen-bonding, and ionic interactions with the AT1 receptor are considered.
View Morepuyang hongda shengdao new material co.,ltd.
Contact:+86-393- 4896278
Address:No.29 East Zhongyuan Road
Hubei Danao Pharmaceutical Co.,Ltd.
website:http://www.danaopharm.com
Contact:+86-719-5251167
Address:Fandan Road,Danjiangkou,Hubei
Xinjiang Zhongtai Chemical Co., Ltd.
Contact:+86-991-8788172
Address:NO.78 XISHAN RD.URUMQI,CHINA
Contact:852-27701081
Address:Room 2509, New Tech Plaza, 34 Tai Yau St., San Po Kong, HK
Zhejiang Haizhou Pharmaceutical Co., Ltd.
website:https://www.haizhoupharma.com/
Contact:+86 576 88221016
Address:No. 19, Donghai 5th Avenue, Yanhai Industrial Zone, Linhai, Zhejiang, China
Doi:10.1002/chem.201600429
(2016)Doi:10.1016/j.bmc.2007.12.042
(2008)Doi:10.1016/j.tetasy.2008.04.031
(2008)Doi:10.1007/s12039-012-0270-0
(2012)Doi:10.1139/v56-056
(1956)Doi:10.1016/S0040-4039(00)94853-6
(1985)