NONPEPTIDE ANGIOTENSIN-II ANTAGONISTS DERIVED FROM 4H-1,2,4-TRIAZOLES AND 3H-IMIDAZO[1,2-B][1,2,4]TRIAZOLES
NONPEPTIDE ANGIOTENSIN-II ANTAGONISTS DERIVED FROM 4H-1,2,4-TRIAZOLES AND 3H-IMIDAZO[1,2-B][1,2,4]TRIAZOLES
复制标题
DOI：
10.1021/jm00057a009
复制
发表时间：
1993-03-05
影响因子：
7.3
通讯作者：
SIEGL, PKS
中科院分区：
文献类型：
--
作者：
ASHTON, WT;CANTONE, CL;SIEGL, PKS
通过多种合成路线，我们合成了一系列3，4，5-三取代的4 H-1，2，4-三唑和相关的一系列3 H-咪唑并[1，2-B] [1，2，4]三唑，并在体外和体内评价了它们作为血管紧张素II（AII）拮抗剂的活性。主要工作集中在C3处带有正烷基取代基和N4处带有4-[（2-羧基苯甲酰基）氨基]苄基、（2 '-羧基联苯-4-基）甲基或[2'-（1H-四唑-5-基）联苯-4-基]甲基侧链的三唑。在C5的众多变化中，苄硫基给出最佳效力。特别值得注意的是3-正丁基-5-[（2-羧基-苄基）硫基]-4-[[2 '-（1H-四唑-5-基）联苯-4-基]甲基]-4H-1，2，4-三唑（71，IC 50 1.4 nM），其在0.3 mg/kg iv剂量下阻断清醒大鼠的AII升压反应，作用持续时间约为6 h，与DuP 753相似。尽管71仅在高10倍的剂量水平下具有口服活性，但对于一元酸类似物62证明了良好的口服生物利用度。双环衍生物中最有效的是2-正丁基-5，6-二甲基-3-[ [2 '-（1H-四唑-5-基）联苯-4-基]甲基]-3H-咪唑并[1，2-B][1，2，4]三唑（93，IC 50 7.8 nM）。考虑了与AT 1受体的疏水、氢键和离子相互作用的影响。
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-carboxy-benzyl)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.