Synthesis and antihypertensive activity of pyrimidin-4(3H)-one derivatives as losartan analogue for new angiotensin II receptor type 1 (AT1) antagonists |
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Authors: | Kim Tae Woo Yoo Byoung Wook Lee Joon Kwang Kim Ji Han Lee Kyung-Tae Chi Yong Ha Lee Jae Yeol |
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Institution: | Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul, Republic of Korea. |
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Abstract: | The discovery, in vitro and in vivo studies of the highly potent AT(1) antagonist 12a (BR-A-657, Fimasartan) antagonists are presented. A series of pyrimidin-4(3H)-one derivatives as losartan analogue were synthesized and evaluated for a novel class of AT(1) receptor antagonists. Among them, 12a containing thioamido moiety displayed both high in vitro functional antagonism and binding affinity IC(50)=0.42 and 0.13 nM, respectively] and inhibited strongly in vivo AngII-induced pressor response in pithed rats with an ED(50) of 0.018 mg/kg. Moreover, in vivo evaluation in furosemide-treated rat and conscious renal hypertensive rat models and the pharmacokinetic study showed that 12a is a highly potent and orally active AT(1) selective antagonist having stronger in vivo potency than losartan. |
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