Diphenylpropionic acids as new AT(1) selective angiotensin II antagonists
Diphenylpropionic acids as new AT(1) selective angiotensin II antagonists
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DOI：
10.1021/jm9508853
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发表时间：
1996-05-24
影响因子：
7.3
通讯作者：
Forn, J
中科院分区：
文献类型：
--
作者：
Almansa, C;Gomez, LA;Forn, J
报道了一系列AT（1）选择性二苯基丙酸类非肽类血管紧张素Ⅱ受体拮抗剂的合成及药理学评价。评价了新化合物的体外AT（1）（大鼠肝脏）和AT（2）（大鼠肾上腺）结合亲和力以及对血管紧张素II诱导的脊髓损伤大鼠平均动脉血压升高的体内抑制作用。二苯基丙酸的不饱和以及侧苯基环被烷基取代或置换导致效力降低。另一方面，在羧酸的α-位上存在小烷基对于活性是重要的，其中所得非对映异构体（R*，R*）之一约为1.5。10-比另一个（R*，S*）活性高1倍。在呋塞米处理的钠耗尽大鼠模型中对最具活性的化合物的口服评价显示，化合物36 g（UR-7198）剂量依赖性地降低血压。该化合物显示出与参比化合物氯沙坦相似的体外和静脉内效力，但起效更快，口服活性更强，可能是由于其生物利用度提高。
The synthesis and pharmacological evaluation of a new series of potent AT(1) selective diphenylpropionic acid nonpeptide angiotensin II receptor antagonists are reported. The new compounds were evaluated for in vitro AT(1) (rat liver) and AT(2) (rat adrenal) binding affinity as well as for in vivo inhibition of angiotensin II-induced increase in mean arterial blood pressure in pithed rats. Unsaturation of the diphenylpropionic acids as well as substitution or replacement by alkyl groups of the pendant phenyl ring resulted in a decrease of potency. On the other hand, the presence of small alkyl groups in the alpha-position to the carboxylic acid was important for activity, with one of the resultant diastereoisomers (R*,R*) being ca. 10-fold more active than the other (R*,S*). Oral evaluation of the most active compounds in a furosemide-treated sodium-depleted rat model showed that compound 36g (UR-7198) reduced blood pressure dose dependently. This compound showed in vitro and iv potencies similar to that of the reference compound losartan but faster onset of action and somewhat greater oral activity, presumably due to its improved bioavailability.