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CARDIOVASCULAR
Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania (C.K.D., B.P.D., M.F.A., A.L.D., M.R.D., H.-C.Z., B.E.M., P.A.-G.); and Charles River Laboratories, Worcester, Massachusetts (M.N.)
Although it is well recognized that human platelet responses to
-thrombin are mediated by the protease-activated receptors PAR-1 and
PAR-4, their role and relative importance in plateletdependent human disease
has not yet been elucidated. Because the expression profile of PARs in
platelets from nonprimates differs from humans, we used cynomolgus monkeys to
evaluate the role of PAR-1 in thrombosis. Based on reverse
transcription-polymerase chain reaction, PAR expression in platelets from
cynomolgus monkeys consisted primarily of PAR-1 and PAR-4, thereby mirroring
the profile of human platelets. We probed the role of PAR-1 in a primate model
of vascular injury-induced thrombosis with the selective PAR-1 antagonist
(S)-N-[(1S)-3-amino-1-[[(phenylmethyl)amino]carbonyl]propyl]--[[[[[1-(2,6-dichlorophenyl)methyl]-3-(1-pyrrolidinylmethyl)-1H-indazol-6-yl]amino]carbonyl]amino]-3,4-difluorobenzenepropanamide
(RWJ-58259). After pretreatment with RWJ-58259 or vehicle, both carotid
arteries of anesthetized monkeys were electrolytically injured and blood flow
was monitored for 60 min. Time to occlusion was significantly extended after
RWJ-58259 administration (27 ± 3 to 53 ± 8 min; p <
0.048). Vessels from three of the five treated animals remained patent. Ex
vivo platelet aggregation measurements indicated complete PAR-1 inhibition, as
well as an operational PAR-4 response. Immunohistochemical staining of mural
thrombi with antibodies to the platelet marker CD61 and fibrinogen indicated
that RWJ-58259 significantly reduced thrombus platelet deposition. Drug
treatment had no effect on key hematological or coagulation parameters. Our
results provide direct evidence that PAR-1 is the primary receptor that
mediates -thrombin's prothrombotic actions in primates and suggest that
PAR-1 antagonists may have potential for the treatment of thrombotic disorders
in humans.
Address correspondence to: Dr. Patricia Andrade-Gordon, Vice President, Drug Discovery, Johnson Johnson Pharmaceutical Research and Development, Welsh and McKean Rds., P.O. Box 776, Spring House, PA 19477. E-mail: pandrade{at}prdus.jnj.com
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