Pyrrolidine-3-carboxylic acids as endothelin antagonists.: 4.: Side chain conformational restriction leads to ETB selectivity

被引：87

作者：

von Geldern, TW ^{[1
]}

Tasker, AS ^{[1
]}

Sorensen, BK ^{[1
]}

Winn, M ^{[1
]}

Szczepankiewicz, BG ^{[1
]}

Dixon, DB ^{[1
]}

Chiou, WJ ^{[1
]}

Wang, LM ^{[1
]}

Wessale, JL ^{[1
]}

Adler, A ^{[1
]}

Marsh, KC ^{[1
]}

Nguyen, E ^{[1
]}

Opgenorth, TJ ^{[1
]}

机构：

[1] Abbott Labs, Pharmaceut Prod Res Div, Metab Dis Res & Drug Anal Dept, Abbott Pk, IL 60064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1999年 / 42卷 / 18期

关键词：

D O I：

10.1021/jm990170q

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

When the dialkylacetamide side chain of the ETA-selective antagonist ABT-627 is replaced with a 2,6-dialkylacetanilide, the resultant analogues show a complete reversal of receptor selectivity, preferring ETB over ETA. By optimizing the aniline substitution pattern, as well as the alkoxy group on the 2-aryl substituent, it is possible to prepare antagonists with subnanomolar affinity for ETB and with selectivities in excess of 4000-fold. A number of these compounds also show promising pharmacokinetic profiles; a useful balance of properties is found in A-192621 (38). Pharmacology studies with A-192621 serve to reveal the role of the ETB receptor in modulating blood pressure; the observed hypertensive response to persistent ETB blockade is consistent with previous postulates and indicates that ETB-selective antagonists may not be suitable as agents for long-term systemic therapy.

引用

页码：3668 / 3678

页数：11

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