Thrombin active site inhibitors: chemical synthesis, in vitro and in vivo pharmacological profile of a novel and selective agent BMS-189090 and analogues.
A series of structurally novel small molecule inhibitors of human alpha-thrombin was prepared to elucidate their structure- activity relationships (SAR), selectivity and activity in vivo. BMS-189090 (5) is identified as a potent, selective, and reversible inhibitor of human alpha-thrombin that is efficacious in vivo in a mice lethality model, and in inhibiting both arterial and venous thrombosis in a rat model.
Das
Jagabandhu
J
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. jagabandhu.das@bms.com
Kimball
S David
SD
Reid
Joyce A
JA
Wang
Tammy C
TC
Lau
Wan F
WF
Roberts
Daniel G M
DG
Seiler
Steven M
SM
Schumacher
William A
WA
Ogletree
Martin L
ML
D000818:Animals; D001665:Binding Sites; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009557:Nipecotic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D012694:Serine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013927:Thrombosis / Q000188:drug therapy / Q000517:prevention & control
C101286:BMS 189090; D005343:Fibrinolytic Agents; D009557:Nipecotic Acids; D015842:Serine Proteinase Inhibitors; D012694:Serine; D013917:Thrombin