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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container_end_page 3161
container_issue 12
container_start_page 3156
container_title Bioorganic & medicinal chemistry letters
container_volume 16
creator 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
description 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.
doi_str_mv 10.1016/j.bmcl.2006.03.045
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title Synthesis of pyrazoles and isoxazoles as potent alpha sub(v) beta sub(3) receptor antagonists
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