Design and discovery of novel, potent pyrazinone-based thrombin inhibitors with a solubilizing amino P1-P2-linker

被引：6

作者：

Bulat, S. ^{[1
]}

Bosio, S. ^{[1
]}

Papadopoulos, M. A. ^{[1
]}

Cerezo-Galvez, S. ^{[1
]}

Grabowski, E. ^{[1
]}

Rosenbaum, C. ^{[1
]}

Matassa, V. G. ^{[1
]}

Ott, I. ^{[1
]}

Metz, G. ^{[1
]}

Schamberger, J. ^{[1
]}

Sekul, R. ^{[1
]}

Feurer, A. ^{[1
]}

机构：

[1] Santhera Pharmaceut Schweiz GmbH, CH-4410 Liestal, Switzerland

来源：

LETTERS IN DRUG DESIGN & DISCOVERY | 2006年 / 3卷 / 05期

关键词：

thrombin; pyrazinone; X-ray; binding mode; selectivity;

D O I：

10.2174/157018006777574203

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The evolution of a novel class of pyrazinone direct thrombin inhibitors (DTIs) is described. In an effort to improve the solubility and thereby the drug-like properties of pyrazinones that possess non-basic P, residues, a novel amino P-1-P-2 linker has been designed from X-ray thrombin-inhibitor complexes. Biochemical evaluation demonstrated that nanomolar binding affinity was attained, and X-ray co-crystal structures reveal an unprecedented binding mode that involves an interaction of the new amino linker with Glu192 of the active site of thrombin. A family of soluble pyrazinones has thereby emerged.

引用

页码：289 / 292

页数：4

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