SSR182289A, a novel, orally active thrombin inhibitor: in vitro profile and ex vivo anticoagulant activity.
SSR182289A competitively inhibits human thrombin (K(i) = 0.031 +/- 0.002 microM) and shows good selectivity with respect to other human proteases, e.g., trypsin (K(i) = 54 +/- 2 microM), factor Xa (K(i) = 167 +/- 9 microM), and factor VIIa, factor IXa, plasmin, urokinase, tPA, kallikrein, and activated protein C (all K(i) values >250 microM). In human plasma, SSR182289A demonstrated anticoagulant activity in vitro as measured by standard clotting parameters (EC100 thrombin time 96 +/- 7 nM) and inhibited tissue factor-induced thrombin generation (IC50 of 0.15 +/- 0.02 microM). SSR182289A inhibited thrombin-induced aggregation of human platelets with an IC50 value of 32 +/- 9 nM, but had no effect on aggregation induced by other platelet agonists. The anticoagulant effects of SSR182289A were studied by measuring changes in coagulation markers ex vivo after i.v. or oral administration in several species. In dogs, SSR182289A (0.1-1 mg/kg i.v. and 1-5 mg/kg p.o.) produced dose-related increases in clotting times. After oral dosing, maximum anticoagulant effects were observed 2 h after administration with increases in thrombin time, 2496 +/- 356%; ecarin clotting time (ECT), 1134 +/- 204%; and activated partial thromboplastin time (aPTT), 91 +/- 20% for the dose of 3 mg/kg p.o., and thrombin time, 3194 +/- 425%; ECT, 2017 +/- 341%; and aPTT, 113 +/- 9% after 5 mg/kg p.o. Eight hours after administration of 3 or 5 mg/kg SSR182289A, clotting times were still elevated. SSR182289A also showed oral anticoagulant activity in rat, rabbit, and macaque. Hence, SSR182289A is a potent, selective, and orally active thrombin inhibitor.
Berry
Christopher N
CN
Sanofi-Synthélabo Research, Cardiovascular-Thrombosis Department, Chilly-Mazarin and Toulouse, France.
Lassalle
Gilbert
G
Lunven
Catherine
C
Altenburger
Jean-Michel
JM
Guilbert
Frédérique
F
Lalé
Alain
A
Hérault
Jean-Pascal
JP
Lecoffre
Catherine
C
Pfersdorff
Christian
C
Herbert
Jean-Marc
JM
O'Connor
Stephen E
SE
D000284:Administration, Oral; D000631:Aminopyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008251:Macaca; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000502:physiology; D013918:Thrombin Time
D000631:Aminopyridines; D000925:Anticoagulants; C469682:N-(3-((((4-(5-amino-2-pyridinyl)-1-((4-difluoromethylene)-1-piperidinyl)carbonyl)butyl)amino)sulfonyl)(1,1'-biphenyl)-2-yl) acetamide; D013449:Sulfonamides; D013917:Thrombin