1ta6

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spinqualitylabelsall models 1ta6, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure of thrombin in complex with compound 14b

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

As part of an ongoing effort to prepare therapeutically useful orally, active thrombin inhibitors, we have synthesized a series of compounds that, utilize nonbasic groups in the P1 position. The work is based on our, previously reported lead structure, compound 1, which was discovered via a, resin-based approach to varying P1. By minimizing the size and, lipophilicity of the P3 group and by incorporating hydrogen-bonding groups, on the N-terminus or on the 2-position of the P1 aromatic ring, we have, prepared a number of derivatives in this series that exhibit subnanomolar, enzyme potency combined with good in vivo antithrombotic and, bioavailability profiles. The oxyacetic amide compound 14b exhibited the, best overall profile of in vitro and in vivo activity, and, crystallographic studies indicate a unique mode of binding in the thrombin, active site.

Disease

Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]

About this Structure

1TA6 is a Single protein structure of sequence from Homo sapiens with 177 as ligand. Active as Thrombin, with EC number 3.4.21.5 Full crystallographic information is available from OCA.

Reference

Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position., Tucker TJ, Brady SF, Lumma WC, Lewis SD, Gardell SJ, Naylor-Olsen AM, Yan Y, Sisko JT, Stauffer KJ, Lucas BJ, Lynch JJ, Cook JJ, Stranieri MT, Holahan MA, Lyle EA, Baskin EP, Chen IW, Dancheck KB, Krueger JA, Cooper CM, Vacca JP, J Med Chem. 1998 Aug 13;41(17):3210-9. PMID:9703466

Page seeded by OCA on Mon Nov 12 19:22:41 2007