Synthesis of pyrazoles and isoxazoles as potent alpha(v)beta3 receptor antagonists.
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.
Penning
Thomas D
TD
Department of Medicinal Chemistry, Pfizer Global Research & Development, 4901 Searle Parkway, Skokie, IL 60077, USA. thomas.penning@abbott.com
Khilevich
Albert
A
Chen
Barbara B
BB
Russell
Mark A
MA
Boys
Mark L
ML
Wang
Yaping
Y
Duffin
Tiffany
T
Engleman
V Wayne
VW
Finn
Mary Beth
MB
Freeman
Sandra K
SK
Hanneke
Melanie L
ML
Keene
Jeffery L
JL
Klover
Jon A
JA
Nickols
G Allen
GA
Nickols
Maureen A
MA
Rader
Randall K
RK
Settle
Steven L
SL
Shannon
Kristen E
KE
Steininger
Christina N
CN
Westlin
Marisa M
MM
Westlin
William F
WF
D000818:Animals; D002460:Cell Line; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D039302:Integrin alphaVbeta3; D007555:Isoxazoles; D011720:Pyrazoles; C031280:pyrazole