3494 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 14
Letters
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In conclusion, tiplaxtinin (3.9) was identified as a
potent and selective PAI-1 inhibitor using a variety of
in vitro assays, and in vivo efficacy was demonstrated
in multiple models of acute arterial thrombosis. Oral
efficacy was observed in an in vivo rat thrombosis model
at plasma concentrations near the IC50. In the canine
coronary artery thrombosis model, treatment with
tiplaxtinin was associated with spontaneous reperfusion
of the occluded coronary vessel indicative of active
fibrinolysis. Tiplaxtinin has exceptional oral bioavail-
ability, is metabolically stable, exhibits large safety
multiples in animal toxicology studies, and is easily
synthesized in bulk quantity. These chemical and
physiological characteristics of tiplaxtinin, together with
its unique profibrinolytic activity without associated
bleeding, make it an excellent candidate for clinical
development.
Ack n ow led gm en t. The authors thank the members
of the Wyeth Discovery Analytical Chemistry Depart-
ment for their assistance in the structural confirmation
of the compounds described in this manuscript. NBD-
labeled PAI-1 mutants were obtained from Dr. Daniel
A. Lawrence, American Red Cross Labs, Bethesda, MD.
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3.9, methods for direct PAI-1 in vitro activity assays, and in
vivo thrombosis models. This material is available free of
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