Retro-binding thrombin active site inhibitors: identification of an orally active inhibitor of thrombin catalytic activity.
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.
Iwanowicz
Edwin J
EJ
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. iwanowie@bms.com
Kimball
S David
SD
Lin
James
J
Lau
Wan
W
Han
W-C
WC
Wang
Tammy C
TC
Roberts
Daniel G M
DG
Schumacher
W A
WA
Ogletree
Martin L
ML
Seiler
Steven M
SM
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002384:Catalysis; D006801:Humans; D051379:Mice; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000633:toxicity
C092032:BMS 183507; C471987:GYKI-14776; D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; D013917:Thrombin