Discovery and initial structure-activity relationships of trisubstituted ureas as thrombin receptor (PAR-1) antagonists

J C Barrow; P G Nantermet; H G Selnick; K L Glass; P L Ngo; M B Young; J M Pellicore; M J Breslin; J H Hutchinson; R M Freidinger; C Condra; J Karczewski; R A Bednar; S L Gaul; A Stern; R Gould; T M Connolly

doi:10.1016/s0960-894x(01)00538-8

Discovery and initial structure-activity relationships of trisubstituted ureas as thrombin receptor (PAR-1) antagonists

Bioorg Med Chem Lett. 2001 Oct 22;11(20):2691-6. doi: 10.1016/s0960-894x(01)00538-8.

Authors

J C Barrow¹, P G Nantermet, H G Selnick, K L Glass, P L Ngo, M B Young, J M Pellicore, M J Breslin, J H Hutchinson, R M Freidinger, C Condra, J Karczewski, R A Bednar, S L Gaul, A Stern, R Gould, T M Connolly

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. [email protected]

PMID: 11591503
DOI: 10.1016/s0960-894x(01)00538-8

Abstract

Thrombin is the most potent agonist of platelet activation, and its effects are predominantly mediated by platelet thrombin receptors. Therefore, antagonists of the thrombin receptor have potential utility for the treatment of thrombotic disorders. Screening of combinatorial libraries revealed 2 to be a potent antagonist of the thrombin receptor. Modifications of this structure produced 11k, which inhibits thrombin receptor stimulated secretion and aggregation of platelets.

MeSH terms

Platelet Activation / drug effects
Receptor, PAR-1
Receptors, Thrombin / antagonists & inhibitors*
Structure-Activity Relationship
Urea / chemistry
Urea / pharmacology*

Substances

Receptor, PAR-1
Receptors, Thrombin
Urea