吡咯烷-3-羧酸作为内皮素拮抗剂。5. 高选择性、强效且口服活性的ET(A)拮抗剂。

Pyrrolidine-3-carboxylic acids as endothelin antagonists. 5. Highly selective, potent, and orally active ET(A) antagonists.

作者信息

Jae H S, Winn M, von Geldern T W, Sorensen B K, Chiou W J, Nguyen B, Marsh K C, Opgenorth T J

机构信息

Metabolic Diseases Research and Drug Analysis Department, Pharmaceutical Products Research Division, Abbott Laboratories, Abbott Park, Illinois 60064-6098, USA.

出版信息

J Med Chem. 2001 Nov 8;44(23):3978-84. doi: 10.1021/jm010237l.

DOI:10.1021/jm010237l

PMID:11689084

Abstract

The synthesis and structure-activity relationships (SAR) of a series of pyrrolidine-3-carboxylic acids as endothelin antagonists are described. The data shows an increase in selectivity when the methoxy of Atrasentan (ABT-627) is replaced with methyl, and the benzodioxole is replaced with dihydrobenzofuran. Adding a fluorine further increases the binding activity and provides a metabolically stable and orally bioavailable ET(A)-selective antagonist.

摘要

描述了一系列作为内皮素拮抗剂的吡咯烷-3-羧酸的合成及其构效关系（SAR）。数据表明，当阿曲生坦（ABT-627）的甲氧基被甲基取代，且苯并二恶唑被二氢苯并呋喃取代时，选择性增加。添加一个氟原子进一步提高了结合活性，并提供了一种代谢稳定且口服生物可利用的ET(A)选择性拮抗剂。