Synthesis of pyrazoles and isoxazoles as potent αvβ3 receptor antagonists

We describe a series of pyrazole and isoxazole analogs as antagonists of the αvβ3 receptor. Compounds showed low to sub-nanomolar potency against αvβ3, as well as good selectivity against αIIbβ3. In HT29 cells, most analogs also demonstrated significant selectivity against αvβ6. Several compounds showed good pharmacokinetic properties in rats, in addition to anti-angiogenic activity in a mouse corneal micropocket model. Compounds were synthesized in a straightforward manner from readily available glutarate precursors.

The synthesis and biological evaluation of a series of pyrazole and isoxazole αvβ3 antagonists is described.Figure optionsDownload as PowerPoint slide