Retro-binding thrombin active site inhibitors: identification of an orally active inhibitor of thrombin catalytic activity

Edwin J Iwanowicz; S David Kimball; James Lin; Wan Lau; W-C Han; Tammy C Wang; Daniel G M Roberts; W A Schumacher; Martin L Ogletree; Steven M Seiler

doi:10.1016/s0960-894x(02)00651-0

Retro-binding thrombin active site inhibitors: identification of an orally active inhibitor of thrombin catalytic activity

Bioorg Med Chem Lett. 2002 Nov 4;12(21):3183-6. doi: 10.1016/s0960-894x(02)00651-0.

Authors

Edwin J Iwanowicz¹, S David Kimball, James Lin, Wan Lau, W-C Han, Tammy C Wang, Daniel G M Roberts, W A Schumacher, Martin L Ogletree, Steven M Seiler

Affiliation

¹ Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. [email protected]

PMID: 12372529
DOI: 10.1016/s0960-894x(02)00651-0

Abstract

A series of retro-binding inhibitors of human alpha-thrombin was prepared to elucidate structure-activity relationships (SAR) and optimize in vivo performance. Compounds 9 and 11, orally active inhibitors of thrombin catalytic activity, were identified to be efficacious in a thrombin-induced lethality model in mice.

MeSH terms

Animals
Binding Sites / drug effects
Catalysis
Humans
Mice
Oligopeptides / chemical synthesis*
Oligopeptides / pharmacology*
Serine Proteinase Inhibitors / chemical synthesis*
Serine Proteinase Inhibitors / pharmacology*
Structure-Activity Relationship
Thrombin / antagonists & inhibitors*
Thrombin / chemistry
Thrombin / toxicity

Substances

BMS 183507
GYKI-14776
Oligopeptides
Serine Proteinase Inhibitors
Thrombin