title: Molecular design and structure--activity relationships leading to the potent, selective, and orally active thrombin active site inhibitor BMS-189664.
abstract: 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.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. jagabandhu.das@bms.com
authors.forename: Jagabandhu
authors.initials: J
authors.lastname: Das
authors.forename: S David
authors.initials: SD
authors.lastname: Kimball
authors.forename: Steven E
authors.initials: SE
authors.lastname: Hall
authors.forename: Wen Ching
authors.initials: WC
authors.lastname: Han
authors.forename: Edwin
authors.initials: E
authors.lastname: Iwanowicz
authors.forename: James
authors.initials: J
authors.lastname: Lin
authors.forename: Robert V
authors.initials: RV
authors.lastname: Moquin
authors.forename: Joyce A
authors.initials: JA
authors.lastname: Reid
authors.forename: John S
authors.initials: JS
authors.lastname: Sack
authors.forename: Mary F
authors.initials: MF
authors.lastname: Malley
authors.forename: Chiehying Y
authors.initials: CY
authors.lastname: Chang
authors.forename: Saeho
authors.initials: S
authors.lastname: Chong
authors.forename: David B
authors.initials: DB
authors.lastname: Wang-Iverson
authors.forename: Daniel G M
authors.initials: DG
authors.lastname: Roberts
authors.forename: Steven M
authors.initials: SM
authors.lastname: Seiler
authors.forename: William A
authors.initials: WA
authors.lastname: Schumacher
authors.forename: Martin L
authors.initials: ML
authors.lastname: Ogletree
mesh_terms: 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
chemical_list: C465967:BMS 189664; D004151:Dipeptides; D005343:Fibrinolytic Agents; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D013917:Thrombin