非肽血管紧张素II受体拮抗剂:一类新的抗高血压药物。

Blood vessels Pub Date : 1990-01-01 DOI:10.1159/000158821
P B Timmermans, D J Carini, A T Chiu, J V Duncia, W A Price, G J Wells, P C Wong, R R Wexler, A L Johnson
{"title":"非肽血管紧张素II受体拮抗剂:一类新的抗高血压药物。","authors":"P B Timmermans,&nbsp;D J Carini,&nbsp;A T Chiu,&nbsp;J V Duncia,&nbsp;W A Price,&nbsp;G J Wells,&nbsp;P C Wong,&nbsp;R R Wexler,&nbsp;A L Johnson","doi":"10.1159/000158821","DOIUrl":null,"url":null,"abstract":"<p><p>The most direct approach to block the function of the renin-angiotensin system would be to antagonize angiotensin II (AII) at the level of its receptor. However, the AII receptor antagonists currently available, such as saralasin, are peptides which still retain agonistic activity and lack oral bioavailability. We have identified the N-benzylimidazoles, S-8307 and S-8308, as weak, but selective nonpeptide AII receptor antagonists. These initial leads were subsequently converted into more potent compounds, such as EXP6155, EXP6803 and EXP7711, while maintaining the selectivity. The compounds displace 3H-AII from its specific binding sites in adrenal cortical membranes and smooth muscle cells. They competitively inhibit the vasoconstrictor response to AII in various in vivo and in vitro preparations, but do not influence those to KCl, norepinephrine, and vasopressin. Converting enzyme and renin are not affected by these agents. In renal hypertensive rats and sodium-depleted dogs our compounds cause a sustained decrease in arterial pressure following intravenous and oral (EXP7711) administration, and are devoid of agonistic properties. Taken together, these nonpeptide structures are true competitive AII receptor antagonists and represent a new class of effective antihypertensive agents.</p>","PeriodicalId":9009,"journal":{"name":"Blood vessels","volume":"27 2-5","pages":"295-300"},"PeriodicalIF":0.0000,"publicationDate":"1990-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000158821","citationCount":"16","resultStr":"{\"title\":\"Nonpeptide angiotensin II receptor antagonists: a novel class of antihypertensive agents.\",\"authors\":\"P B Timmermans,&nbsp;D J Carini,&nbsp;A T Chiu,&nbsp;J V Duncia,&nbsp;W A Price,&nbsp;G J Wells,&nbsp;P C Wong,&nbsp;R R Wexler,&nbsp;A L Johnson\",\"doi\":\"10.1159/000158821\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The most direct approach to block the function of the renin-angiotensin system would be to antagonize angiotensin II (AII) at the level of its receptor. However, the AII receptor antagonists currently available, such as saralasin, are peptides which still retain agonistic activity and lack oral bioavailability. We have identified the N-benzylimidazoles, S-8307 and S-8308, as weak, but selective nonpeptide AII receptor antagonists. These initial leads were subsequently converted into more potent compounds, such as EXP6155, EXP6803 and EXP7711, while maintaining the selectivity. The compounds displace 3H-AII from its specific binding sites in adrenal cortical membranes and smooth muscle cells. They competitively inhibit the vasoconstrictor response to AII in various in vivo and in vitro preparations, but do not influence those to KCl, norepinephrine, and vasopressin. Converting enzyme and renin are not affected by these agents. In renal hypertensive rats and sodium-depleted dogs our compounds cause a sustained decrease in arterial pressure following intravenous and oral (EXP7711) administration, and are devoid of agonistic properties. Taken together, these nonpeptide structures are true competitive AII receptor antagonists and represent a new class of effective antihypertensive agents.</p>\",\"PeriodicalId\":9009,\"journal\":{\"name\":\"Blood vessels\",\"volume\":\"27 2-5\",\"pages\":\"295-300\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"1990-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1159/000158821\",\"citationCount\":\"16\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Blood vessels\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1159/000158821\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Blood vessels","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1159/000158821","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 16

摘要

阻断肾素-血管紧张素系统功能的最直接方法是在受体水平上拮抗血管紧张素II (AII)。然而,目前可用的AII受体拮抗剂,如saralasin,是仍然保留激动活性且缺乏口服生物利用度的肽。我们已经确定n -苄基咪唑,S-8307和S-8308是弱的,但选择性的非肽AII受体拮抗剂。这些初始先导物随后被转化为更有效的化合物,如EXP6155、EXP6803和EXP7711,同时保持了选择性。这些化合物取代3H-AII在肾上腺皮质膜和平滑肌细胞中的特定结合位点。在各种体内和体外制剂中,它们竞争性地抑制血管收缩剂对AII的反应,但不影响对KCl、去甲肾上腺素和抗利尿激素的反应。转化酶和肾素不受这些药物的影响。在肾性高血压大鼠和钠耗尽犬中,我们的化合物在静脉和口服(EXP7711)给药后可持续降低动脉压,并且不具有激动剂特性。综上所述,这些非肽结构是真正的竞争性AII受体拮抗剂,代表了一类新的有效抗高血压药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Nonpeptide angiotensin II receptor antagonists: a novel class of antihypertensive agents.

The most direct approach to block the function of the renin-angiotensin system would be to antagonize angiotensin II (AII) at the level of its receptor. However, the AII receptor antagonists currently available, such as saralasin, are peptides which still retain agonistic activity and lack oral bioavailability. We have identified the N-benzylimidazoles, S-8307 and S-8308, as weak, but selective nonpeptide AII receptor antagonists. These initial leads were subsequently converted into more potent compounds, such as EXP6155, EXP6803 and EXP7711, while maintaining the selectivity. The compounds displace 3H-AII from its specific binding sites in adrenal cortical membranes and smooth muscle cells. They competitively inhibit the vasoconstrictor response to AII in various in vivo and in vitro preparations, but do not influence those to KCl, norepinephrine, and vasopressin. Converting enzyme and renin are not affected by these agents. In renal hypertensive rats and sodium-depleted dogs our compounds cause a sustained decrease in arterial pressure following intravenous and oral (EXP7711) administration, and are devoid of agonistic properties. Taken together, these nonpeptide structures are true competitive AII receptor antagonists and represent a new class of effective antihypertensive agents.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
自引率
0.00%
发文量
0
期刊最新文献
Contractile and morphologic properties of a saphenous vein after 12 years as an aortocoronary bypass graft. Effect of H-8, an isoquinolinesulfonamide inhibitor of cyclic nucleotide-dependent protein kinase, on cAMP- and cGMP-mediated vasorelaxation. Hemorheological effects of buflomedil: action on shape and functions of the human neutrophils. Norepinephrine, phentolamine and buflomedil influence on arteriolar vasomotion in the hamster skinfold preparation. Heme-dependent activation of guanylate cyclase by nitric oxide: a novel signal transduction mechanism.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1