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Synthesis of pyrazoles and isoxazoles as potent alpha(v)beta3 receptor antagonists |
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| Authors: | Penning Thomas D Khilevich Albert Chen Barbara B Russell Mark A Boys Mark L Wang Yaping Duffin Tiffany Engleman V Wayne Finn Mary Beth Freeman Sandra K Hanneke Melanie L Keene Jeffery L Klover Jon A Nickols G Allen Nickols Maureen A Rader Randall K Settle Steven L Shannon Kristen E Steininger Christina N Westlin Marisa M Westlin William F |
| Institution: | Department of Medicinal Chemistry, Pfizer Global Research & Development, 4901 Searle Parkway, Skokie, IL 60077, USA. thomas.penning@abbott.com |
| Abstract: | We describe a series of pyrazole and isoxazole analogs as antagonists of the alpha(v)beta3 receptor. Compounds showed low to sub-nanomolar potency against alpha(v)beta3, as well as good selectivity against alpha(IIb)beta3. In HT29 cells, most analogs also demonstrated significant selectivity against alpha(v)beta6. 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. |
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