Leonard C. Weir

D-Phe-Pro-p-Amidinobenzylamine: A potent and highly selective thrombin inhibitor

Abstract The design, synthesis, and enzyme inhibitory profile of D-Phe-Pro-p-Amidinobenzylamine are presented. This compound has inhibitory activity equivalent to D-Phe-Pro-Arg-H, two orders of magnitude more potent than D-Phe-Pro-Agmatine. The results indicate that binding energy provided by the covalent bond of a transition-state analog can be replaced with noncovalent interactions.

Serine protease selectivity of the thrombin inhibitor D-Phe-Pro-Agmatine and its homologs

Abstract Analogs of D-Phe-Pro-Agmatine were assayed for inhibititory activity versus thrombin, trypsin, plasmin, n-tPA and urokinase. The X-ray structure of the thrombin/D-Phe-Pro-Agmatine co-crystal revealed that the agmatine and analogous arginals have very similar bound conformations.

The design of potent, selective, non-covalent, peptide thrombin inhibitors utilizing imidazole as a S1 binding element

Modeling of neutral or mildly basic functional groups in the S1 site of thrombin led to the targeting of imidazole as a S1 binding element and correctly predicted the optimal chain length for connecting this group with the S2 and S3 binding elements. Derivatives of 4-(3-aminopropyl)-imidazole can be selective inhibitors of thrombin demonstrating potent anticoagulant activity.

N-substituted glycines as replacements for proline in tripeptide aldehyde thrombin inhibitors

Abstract We have prepared a series of tripeptide arginine aldehydes in which the P2 proline has been replaced with a variety of N -substituted glycines. The effects of these modifications on thrombin inhibitory potency and serine protease selectivity were evaluated.