Molecular design and structure--activity relationships leading to the potent, selective, and orally active thrombin active site inhibitor BMS-189664.
A series of structurally novel small molecule inhibitors of human alpha-thrombin was prepared to elucidate their structure-activity relationships (SARs), selectivity and activity in vivo. BMS-189664 (3) is identified as a potent, selective, and orally active reversible inhibitor of human alpha-thrombin which is efficacious in vivo in a mouse lethality model, and at inhibiting both arterial and venous thrombosis in cynomolgus monkey models.
Das
Jagabandhu
J
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. jagabandhu.das@bms.com
Kimball
S David
SD
Hall
Steven E
SE
Han
Wen Ching
WC
Iwanowicz
Edwin
E
Lin
James
J
Moquin
Robert V
RV
Reid
Joyce A
JA
Sack
John S
JS
Malley
Mary F
MF
Chang
Chiehying Y
CY
Chong
Saeho
S
Wang-Iverson
David B
DB
Roberts
Daniel G M
DG
Seiler
Steven M
SM
Schumacher
William A
WA
Ogletree
Martin L
ML
D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D020128:Inhibitory Concentration 50; D008252:Macaca fascicularis; D051379:Mice; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000188:drug therapy / Q000517:prevention & control
C465967:BMS 189664; D004151:Dipeptides; D005343:Fibrinolytic Agents; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D013917:Thrombin