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

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

Volume: 3 Issue: 5

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 and A. Feurer

Affiliation:

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

Abstract: 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.

Cite this article as:

Bulat S., Bosio S., Papadopoulos A. M., Cerezo-Galvez S., Grabowski E., Rosenbaum C., Matassa G. V., Ott I., Metz G., Schamberger J., Sekul R. and Feurer A., Design and Discovery of Novel, Potent Pyrazinone-Based Thrombin Inhibitors with a Solubilizing Amino P1-P2-Linker, Letters in Drug Design & Discovery 2006; 3 (5) . https://dx.doi.org/10.2174/157018006777574203