From natural products to achiral drug prototypes: potent thrombin inhibitors based on P2/P3 dihydropyrid-2-one core motifs

Stephen Hanessian; Eric Therrien; Jianbin Zhang; Willem van Otterlo; Yafeng Xue; David Gustafsson; Ingemar Nilsson; Ola Fjellström

doi:10.1016/j.bmcl.2009.07.107

From natural products to achiral drug prototypes: potent thrombin inhibitors based on P2/P3 dihydropyrid-2-one core motifs

Bioorg Med Chem Lett. 2009 Sep 15;19(18):5429-32. doi: 10.1016/j.bmcl.2009.07.107. Epub 2009 Jul 26.

Authors

Stephen Hanessian¹, Eric Therrien, Jianbin Zhang, Willem van Otterlo, Yafeng Xue, David Gustafsson, Ingemar Nilsson, Ola Fjellström

Affiliation

¹ Department of Chemistry, Université de Montréal, C. P. 6128, Succ. Centre-Ville, Montréal, P. Q., Canada H3C 3J7. stephen.hanessian@umontreal.ca

PMID: 19674897
DOI: 10.1016/j.bmcl.2009.07.107

Abstract

A series of dihydropyrid-2-ones was synthesized and tested for inhibitory activity against serine protease enzymes. Moderate to low nanomolar inhibitory activities were obtained against thrombin and excellent selectivity against trypsin was observed.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cattle
Crystallography, X-Ray
Humans
Models, Molecular
Protein Binding
Pyridones / chemical synthesis
Pyridones / chemistry*
Pyridones / pharmacology*
Serine Proteinase Inhibitors / chemical synthesis
Serine Proteinase Inhibitors / chemistry*
Serine Proteinase Inhibitors / pharmacology*
Thrombin / antagonists & inhibitors*
Thrombin / chemistry
Thrombin / metabolism*
Trypsin / metabolism

Substances

Pyridones
Serine Proteinase Inhibitors
Trypsin
Thrombin