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

Tianbao Lu; Thomas Markotan; Shelley K Ballentine; Edward C Giardino; John Spurlino; Carl S Crysler; Kathryn Brown; Bruce E Maryanoff; Bruce E Tomczuk; Bruce P Damiano; Umesh Shukla; David End; Patricia Andrade-Gordon; Roger F Bone; Mark R Player

doi:10.1021/jm901802n

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

J Med Chem. 2010 Feb 25;53(4):1843-56. doi: 10.1021/jm901802n.

Authors

Tianbao Lu¹, Thomas Markotan, Shelley K Ballentine, Edward C Giardino, John Spurlino, Carl S Crysler, Kathryn Brown, Bruce E Maryanoff, Bruce E Tomczuk, Bruce P Damiano, Umesh Shukla, David End, Patricia Andrade-Gordon, Roger F Bone, Mark R Player

Affiliation

¹ Johnson & Johnson Pharmaceutical Research and Development, Welsh and McKean Roads, Spring House, Pennsylvania 19477-0776, USA.

PMID: 20102150
DOI: 10.1021/jm901802n

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.

Publication types

Randomized Controlled Trial

MeSH terms

Amino Acid Motifs
Animals
Anticoagulants / chemical synthesis*
Anticoagulants / pharmacokinetics
Anticoagulants / pharmacology
Blood Pressure / drug effects
Caco-2 Cells
Crystallography, X-Ray
Cytochrome P-450 CYP3A
Cytochrome P-450 CYP3A Inhibitors
Dogs
Double-Blind Method
Electrocardiography
Female
Fibrinolytic Agents / chemical synthesis*
Fibrinolytic Agents / pharmacokinetics
Fibrinolytic Agents / pharmacology
Guanidines / chemical synthesis*
Guanidines / pharmacokinetics
Guanidines / pharmacology
Guinea Pigs
Heart Rate / drug effects
Hemodynamics / drug effects
Humans
In Vitro Techniques
Male
Microsomes, Liver / metabolism
Models, Molecular
Pyrazines / chemical synthesis*
Pyrazines / pharmacokinetics
Pyrazines / pharmacology
Rats
Rats, Sprague-Dawley
Recombinant Proteins / antagonists & inhibitors
Structure-Activity Relationship
Thrombin / antagonists & inhibitors*
Thrombin / chemistry
Venous Thrombosis / blood
Venous Thrombosis / drug therapy

Substances

1-(N-(2-(Amidinoaminooxy)ethyl)amino)carbonylmethyl-6-methyl-3-(2,2-difluoro-2-phenylethylamino)pyrazinone
Anticoagulants
Cytochrome P-450 CYP3A Inhibitors
Fibrinolytic Agents
Guanidines
Pyrazines
Recombinant Proteins
Cytochrome P-450 CYP3A
CYP3A4 protein, human
Thrombin