Small, low nanomolar, noncovalent thrombin inhibitors lacking a group to fill the 'distal binding pocket'

Philip E J Sanderson; Kellie J Cutrona; Dona L Dyer; Julie A Krueger; Lawrence C Kuo; S Dale Lewis; Bobby J Lucas; Youwei Yan

doi:10.1016/s0960-894x(02)00946-0

Small, low nanomolar, noncovalent thrombin inhibitors lacking a group to fill the 'distal binding pocket'

Bioorg Med Chem Lett. 2003 Jan 20;13(2):161-4. doi: 10.1016/s0960-894x(02)00946-0.

Authors

Philip E J Sanderson¹, Kellie J Cutrona, Dona L Dyer, Julie A Krueger, Lawrence C Kuo, S Dale Lewis, Bobby J Lucas, Youwei Yan

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. phil_sanderson@merck.com

PMID: 12482415
DOI: 10.1016/s0960-894x(02)00946-0

Abstract

Use of a chlorophenoxyacetamide P1 group with a pyridinone acetamide P2/P3 gave an exceptionally potent thrombin inhibitor (K(i)=40 pM). Truncation of the molecule at the N-terminus gave unique, low nanomolar, non-covalent thrombin inhibitors which do not have a group to fill thrombin's 'distal binding pocket'. A co-crystal structure indicates the importance of an intramolecular hydrogen bond between the P1 side chain and P1/P2 amide link in this series.

MeSH terms

Acetamides / chemical synthesis*
Acetamides / pharmacology*
Binding Sites
Crystallization
Crystallography, X-Ray
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Models, Molecular
Molecular Conformation
Pyridones / chemical synthesis*
Pyridones / pharmacology*
Thrombin / antagonists & inhibitors*
Thrombin / chemistry

Substances

Acetamides
Enzyme Inhibitors
Pyridones
Thrombin