Synthesis of pyrazoles and isoxazoles as potent alpha sub(v) beta sub(3) receptor antagonists

Synthesis of pyrazoles and isoxazoles as potent alpha sub(v) beta sub(3) receptor antagonists

We describe a series of pyrazole and isoxazole analogs as antagonists of the alpha sub(v) beta sub(3) receptor. Compounds showed low to sub-nanomolar potency against alpha sub(v) beta sub(3), as well as good selectivity against alpha sub(IIb) beta sub(3). In HT29 cells, most analogs also demonstrate...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2006-06, Vol.16 (12), p.3156-3161
Hauptverfasser: Penning, Thomas D, Khilevich, Albert, Chen, Barbara B, Russell, Mark A, Boys, Mark L, Wang, Yaping, Duffin, Tiffany, Engleman, VWayne, Finn, Mary Beth, Freeman, Sandra K, Hanneke, Melanie L, Keene, Jeffery L, Klover, Jon A, Nickols, GAllen, Nickols, Maureen A, Rader, Randall K, Settle, Steven L, Shannon, Kristen E, Steininger, Christina N, Westlin, Marisa M, Westlin, William F
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Sprache:eng
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Zusammenfassung:We describe a series of pyrazole and isoxazole analogs as antagonists of the alpha sub(v) beta sub(3) receptor. Compounds showed low to sub-nanomolar potency against alpha sub(v) beta sub(3), as well as good selectivity against alpha sub(IIb) beta sub(3). In HT29 cells, most analogs also demonstrated significant selectivity against alpha sub(v) beta sub(6). 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2006.03.045