Synthesis and pharmacological evaluation of 5-(4-biphenyl)-3-methyl-4-phenyl-1,2,4-triazole derivatives as a novel class of selective antagonists for the human vasopressin V(1A) receptor.

Kakefuda A; Suzuki T; Tobe T; Tsukada J; Tahara A; Sakamoto S; Tsukamoto S

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Synthesis and pharmacological evaluation of 5-(4-biphenyl)-3-methyl-4-phenyl-1,2,4-triazole derivatives as a novel class of selective antagonists for the human vasopressin V(1A) receptor.

机译：5-（4-联苯基）-3-甲基-4-苯基-1,2,4-三唑衍生物的合成及其药理学评估，它是一类新的人血管加压素V（1A）受体选择性拮抗剂。

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A series of 5-(4-biphenyl)-3-methyl-4-phenyl-1,2,4-triazole derivatives were prepared and evaluated as selective antagonists for the human vasopressin V(1A) receptor. The compounds were examined for their affinity to the cloned human V(1A) receptor (hV(1A)) and selectivity vs the cloned human V(2) receptor (hV(2)). By utilizing the structure-activity relationship on 4,4-difluoro-5-methylidene-2,3,4,5-tetrahydrobenzazepine derivatives as dual antagonists for the V(1A) and V(2) receptors in our previous study, we found that substituting the methoxy group at the 2-position of the 4-phenyl ring with (4-methylpiperazin-1-yl)alkoxy moieties brought about marked improvement of both affinity to hV(1A) and selectivity vs hV(2). Further introduction of a methyl group into the 6-position of the 4-phenyl ring resulted in additional improvement of selectivity. One particular compound, 5-(4-biphenyl)-3-methyl-4-[2-[6-(4-methyl-1-piperazinyl)hexyloxy]phenyl]-1 ,2,4-triazole (19) showed potent affinity to hV(1A) with a K(i) value of 1.04 nM and high selectivity with a 1700-fold selectivity vs hV(2). We also found marked differences in the affinity of compounds in this series between the human and the rat receptors. Compound 19 was further examined for its V(1A) receptor antagonist activity in rats. As a result, 19 demonstrated antagonist activities toward an arginine vasopressin-induced increase in diastolic blood pressure after intravenous or oral administration and long-lasting oral activity.

机译：制备了一系列5-（4-联苯基）-3-甲基-4-苯基-1,2,4-三唑衍生物，并将其评估为人血管加压素V（1A）受体的选择性拮抗剂。检查化合物对克隆的人V（1A）受体（hV（1A））的亲和力和对克隆的人V（2）受体（hV（2））的选择性。通过在我们以前的研究中利用对4,4-二氟-5-亚甲基-2,3,4,5-四氢苯并ze庚因衍生物的结构-活性关系作为V（1A）和V（2）受体的双重拮抗剂，我们发现用（4-甲基哌嗪-1-基）烷氧基部分取代4-苯环的2-位上的甲氧基带来了对hV（1A）的亲和力和相对于hV（2）的选择性的显着改善。将甲基进一步引入4-苯基环的6-位导致选择性的进一步提高。一种特定的化合物5-（4-联苯基）-3-甲基-4- [2- [6-（4-甲基-1-哌嗪基）己氧基]苯基] -1，2,4-三唑（19）显示出有效的与hV（1A）的亲和力，K（i）值为1.04 nM，高选择性，相对于hV（2）的选择性为1700倍。我们还发现，在人类和大鼠受体之间，该系列化合物的亲和力存在明显差异。进一步检查化合物19在大鼠中的V（1A）受体拮抗剂活性。结果，在静脉或口服给药后，有19种拮抗剂表现出对精氨酸加压素诱导的舒张压升高的拮抗剂活性，以及持久的口服活性。

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《Journal of Medicinal Chemistry》 |2002年第12期|共10页
作者
Kakefuda A; Suzuki T; Tobe T; Tsukada J; Tahara A; Sakamoto S; Tsukamoto S;
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正文语种 eng
中图分类药学;
关键词
1A; receptor; Upper Case Vee; Human; antagonists;

机译：1A;受体;大写字母Vee;人类;拮抗剂;

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机译：5-（4-联苯基）-3-甲基-4-苯基-1,2,4-三唑衍生物的合成及其药理学评估，它是一类新的人血管加压素V（1A）受体选择性拮抗剂。
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Synthesis and pharmacological evaluation of 5-(4-biphenyl)-3-methyl-4-phenyl-1,2,4-triazole derivatives as a novel class of selective antagonists for the human vasopressin V(1A) receptor.

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