title: Discovery and clinical evaluation of 1-{N-[2-(amidinoaminooxy)ethyl]amino}carbonylmethyl-6-methyl-3-[2,2-difluoro-2-phenylethylamino]pyrazinone (RWJ-671818), a thrombin inhibitor with an oxyguanidine P1 motif.
abstract: We have identified RWJ-671818 (8) as a novel, low molecular weight, orally active inhibitor of human alpha-thrombin (K(i) = 1.3 nM) that is potentially useful for the acute and chronic treatment of venous and arterial thrombosis. In a rat deep venous thrombosis model used to assess antithrombotic efficacy, oral administration of 8 at 30 and 50 mg/kg reduced thrombus weight by 87 and 94%, respectively. In an anesthetized rat antithrombotic model, where electrical stimulation of the carotid artery created a thrombus, 8 prolonged occlusion time 2- and 3-fold at 0.1 and 1.0 mg/kg, i.v., respectively, and more than doubled activated clotting time and activated partial thromboplastin time at the higher dose. This compound had excellent oral bioavailability of 100% in dogs with an estimated half-life of approximately 3 h. On the basis of its noteworthy preclinical data, 8 was advanced into human clinical trials and successfully progressed through phase 1 studies.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, Welsh and McKean Roads, Spring House, Pennsylvania 19477-0776, USA.
authors.forename: Tianbao
authors.initials: T
authors.lastname: Lu
authors.forename: Thomas
authors.initials: T
authors.lastname: Markotan
authors.forename: Shelley K
authors.initials: SK
authors.lastname: Ballentine
authors.forename: Edward C
authors.initials: EC
authors.lastname: Giardino
authors.forename: John
authors.initials: J
authors.lastname: Spurlino
authors.forename: Carl S
authors.initials: CS
authors.lastname: Crysler
authors.forename: Kathryn
authors.initials: K
authors.lastname: Brown
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Tomczuk
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Damiano
authors.forename: Umesh
authors.initials: U
authors.lastname: Shukla
authors.forename: David
authors.initials: D
authors.lastname: End
authors.forename: Patricia
authors.initials: P
authors.lastname: Andrade-Gordon
authors.forename: Roger F
authors.initials: RF
authors.lastname: Bone
authors.forename: Mark R
authors.initials: MR
authors.lastname: Player
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004285:Dogs; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006146:Guanidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D011719:Pyrazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020246:Venous Thrombosis / Q000097:blood / Q000188:drug therapy
chemical_list: C547956:1-(N-(2-(Amidinoaminooxy)ethyl)amino)carbonylmethyl-6-methyl-3-(2,2-difluoro-2-phenylethylamino)pyrazinone; D000925:Anticoagulants; D065692:Cytochrome P-450 CYP3A Inhibitors; D005343:Fibrinolytic Agents; D006146:Guanidines; D011719:Pyrazines; D011994:Recombinant Proteins; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D013917:Thrombin