Design and structure-activity relationship of thrombin inhibitors with an azaphenylalanine scaffold: potency and selectivity enhancements via P2 optimization.

Abstract:

:Theoretical and structural studies followed by the directed synthesis and in vitro biological tests lead us to novel noncovalent thrombin pseudopeptide inhibitors. We have incorporated an azapeptide scaffold into the central part of the classical tripeptide D-Phe-Pro-Arg inhibitor structure thus eliminating one stereogenic center from the molecule. A series of compounds has been designed to optimize the occupancy of the S2 pocket of thrombin. Increased hydrophobicity at P2 provides an enhanced fit into this active site S2 pocket. In the present paper, we also report on the structure of these inhibitors in solution and conformational analysis of inhibitors in the active site in order to asses the consequences of the replacement of the central alpha-CH by a nitrogen functionality. In vitro biological testing of the designed inhibitors shows that elimination of R, S stereoisomerism and restriction of conformational freedom influences the binding of inhibitors in a favorable fashion.

journal_name

Bioorg Med Chem

authors

Zega A,Mlinsek G,Sepic P,Golic Grdadolnik S,Solmajer T,Tschopp TB,Steiner B,Kikelj D,Urleb U

doi

10.1016/s0968-0896(01)00202-4

subject

Has Abstract

pub_date

2001-10-01 00:00:00

pages

2745-56

issue

10

eissn

0968-0896

issn

1464-3391

pii

S0968089601002024

journal_volume

9

pub_type

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