Synthesis and structure-activity relationship of a new series of potent AT(1) selective angiotensin II receptor antagonists: 5-(biphenyl-4-ylmethyl)pyrazoles
Synthesis and structure-activity relationship of a new series of potent AT(1) selective angiotensin II receptor antagonists: 5-(biphenyl-4-ylmethyl)pyrazoles
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DOI：
10.1021/jm9604383
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发表时间：
1997-02-14
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
本文报道了一系列新的5-（联苯-4-基甲基）吡唑类化合物作为有效的血管紧张素Ⅱ拮抗剂的合成和药理活性，这些化合物在体外（与[H-3]AII结合）和体内（iv，抑制AII诱导的血压升高，脊髓损伤大鼠; po，呋塞米治疗的钠耗竭大鼠）均具有药理活性。吡唑环的各种取代基已被修改，考虑到来自相关的结构-活性关系研究的受体的要求。在位置1处的丙基或丁基以及在位置4处的羧酸基团被示出对于高亲和力是必需的。3位上的不同基团（H、小烷基、苯基、苄基）提供了良好的结合亲和力，但口服活性具有高度区分性：庞大的烷基提供了最高的效力。在联苯部分中测试的酸性电子等排体中，四唑基团被证明是最好的。化合物14 n（3-叔丁基-1-丙基-5-[[2 '-（1H-四唑-5-基）-1，1'-联苯-4-基]甲基]-1H-吡唑-4-羧酸，UR-7280）在体外和体内均显示出高效价（IC 50 = 3 nM）和体内（iv，0.3 mg/kg时血压下降61.2 ± 10%; po，0.3 mg/kg时血压下降30 mmHg），与氯沙坦相比（IC 50 = 59 nM; iv，1 mg/kg时血压降低62.5 +/- 8.9%; po，3 mg/kg时血压降低13 mmHg）。这些数据，加上良好的药代动力学特征的14 n在不同的物种，导致其选择作为抗高血压药物的临床评价。
The synthesis and pharmacological activity of a new series of 5-(biphenyl-4-ylmethyl)pyrazoles as potent angiotensin II antagonists both in vitro (binding of[H-3]AII) and in vivo (iv, inhibition of AII-induced increase in blood pressure, pithed rats; po, furosemide-treated sodium-depleted rats) are reported. The various substituents of the pyrazole ring have been modified taking into account the receptor's requirements derived from related structure-activity relationship studies. A propyl or butyl group at position 1 as well as a carboxylic acid group at position 4 were shown to be essential for high affinity. Different groups at position 3 (H, small alkyl, phenyl, benzyl) provided good binding affinity, but oral activity was highly discriminating: bulky alkyl groups provided the highest potencies. Among the acidic isosteres tested in the biphenyl moiety, the tetrazole group proved to be the best. Compound 14n (3-tert-butyl-1-propyl-5-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-yl]methyl]-1H-pyrazole-4-carboxylic acid, UR-7280) shows high potency both in vitro (IC50 = 3 nM) and in vivo (iv, 61.2 +/- 10% decrease in blood pressure at 0.3 mg/kg; po, 30 mmHg fall in blood pressure at 0.3 mg/kg), in comparison to losartan (IC50 = 59 nM; iv, 62.5 +/- 8.9% decrease in blood pressure at I mg/kg; po, 13 mmHg fall in blood pressure at 3 mg/kg). These data, together with the good pharmacokinetic profile of 14n in different species, have led to its selection for clinical evaluation as an antihypertensive agent.