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Azole endothelin antagonists. 2. Structure-activity studies.

Abstract：

:Structure-activity studies have been performed in an attempt to improve the potency of a novel series of azole-based endothelin-A (ET(A)) selective antagonists. Modifications of the hydrophobic group on the terminal urea produced substantial effects on receptor affinity; in particular, the choice of cyclohexyl- or arylureas led to substantial improvements in activity. Conformational restriction of these groups provides an additional benefit. N-Methylation of the indole moiety which is part of the heterocyclic dipeptide surrogate also improves potency. The effects of these two modifications appear to be synergistic, with the best of the resultant doubly modified analogs (e.g. 14q, 15y, and 15ff) exhibiting an 80-200-fold improvement over the original leads.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

von Geldern TW,Kester JA,Bal R,Wu-Wong JR,Chiou W,Dixon DB,Opgenorth TJ

doi

10.1021/jm950592+

subject

Has Abstract

pub_date

1996-02-16 00:00:00

pages

968-81

issue

4

eissn

0022-2623

issn

1520-4804

pii

jm950592+

journal_volume

39

pub_type

杂志文章

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