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Design of novel, potent, noncovalent inhibitors of thrombin with nonbasic P-1 substructures: rapid structure-activity studies by solid-phase synthesis.

Abstract：

:Study of surface representations of the inhibitor-bound thrombin P-1 pocket revealed a lipophilic recess in this pocket which is not occupied by any known inhibitor. Solid-phase synthesis was used to generate benzylamides of D-diphenylAlaPro by aminolysis of Boc dipeptide Kaiser resin. The resulting amides inhibited thrombin in the range IC50 = 3-13,000 nM, and the structure-activity relationships and molecular modeling suggest a unique fit of the benzyl side chain into P-1 with the meta substituent occupying the recess.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Lumma WC Jr,Witherup KM,Tucker TJ,Brady SF,Sisko JT,Naylor-Olsen AM,Lewis SD,Lucas BJ,Vacca JP

doi

10.1021/jm9706933

subject

Has Abstract

pub_date

1998-03-26 00:00:00

pages

1011-3

issue

7

eissn

0022-2623

issn

1520-4804

pii

jm9706933

journal_volume

41

pub_type

杂志文章

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