PDBsum entry 2feq

Hydrolase/hydrolase inhibitor

PDB id: 2feq

Contents

Protein chains

28 a.a.

250 a.a.

11 a.a.

Ligands

34P

Waters ×100

References listed in PDB file

Key reference

• Title: Orally active thrombin inhibitors. Part 1: optimization of the p1-Moiety.
• Authors: H.Mack, D.Baucke, W.Hornberger, U.E.Lange, W.Seitz, H.W.Höffken.
• Ref.: Bioorg Med Chem Lett, 2006, 16, 2641-2647. [DOI no: 10.1016/j.bmcl.2006.02.040]
• PubMed id: 16517159

Abstract

The synthesis and SAR of novel nanomolar thrombin inhibitors with the common backbone HOOC-CH(2)-d-cyclohexylalanyl-3,4-dehydroprolyl-NH-CH(2)-aryl-C(=NH)NH(2) are described together with their ecarin clotting time (ECT) prolongation as measure for thrombin inhibition ex vivo. The aryl P1-moiety mimicking the arginine part of the d-Phe-Pro-Arg derived thrombin inhibitors turned out to be a key component for in vitro potency and in vivo activity. Optimization of this part led to compounds with improved antithrombin activity in rats and dogs after oral administration compared to the recently launched anticoagulant melagatran.