Letters in Drug Design & Discovery

G. Perry
University of Texas
San Antonio, TX
Email: lddd@benthamscience.org


Design and Discovery of Novel, Potent Pyrazinone-Based Thrombin Inhibitors with a Solubilizing Amino P1-P2-Linker

Author(s): S. Bulat, S. Bosio, M. A. Papadopoulos, S. Cerezo-Galvez, E. Grabowski, C. Rosenbaum, V. G. Matassa, I. Ott, G. Metz, J. Schamberger, R. Sekul, A. Feurer.


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 P1 residues, a novel amino P1-P2 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.

Keywords: Thrombin, pyrazinone, X-ray, binding mode, selectivity

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Article Details

Year: 2006
Page: [289 - 292]
Pages: 4
DOI: 10.2174/157018006777574203
Price: $58