Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul, Republic of Korea.
Bioorg Med Chem Lett. 2012 Feb 15;22(4):1649-54. doi: 10.1016/j.bmcl.2011.12.116. Epub 2012 Jan 2.
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.
呈现了高度有效的 AT(1)拮抗剂 12a（BR-A-657、非马沙坦）拮抗剂的体外和体内研究发现。合成了一系列嘧啶-4(3H)-酮衍生物作为洛沙坦类似物，并对新型 AT(1)受体拮抗剂进行了评估。其中，含有硫代酰胺部分的 12a 显示出高体外功能拮抗作用和结合亲和力[IC(50)分别为 0.42 和 0.13 nM]，并强烈抑制麻醉大鼠中 AngII 诱导的升压反应，ED(50)为 0.018 mg/kg。此外，在呋塞米处理的大鼠和清醒肾性高血压大鼠模型中的体内评价以及药代动力学研究表明，12a 是一种高效、口服活性的 AT(1)选择性拮抗剂，其体内效力强于洛沙坦。
