title: Synthesis of pyrazoles and isoxazoles as potent alpha(v)beta3 receptor antagonists.
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.
authors.affiliation: Department of Medicinal Chemistry, Pfizer Global Research & Development, 4901 Searle Parkway, Skokie, IL 60077, USA. thomas.penning@abbott.com
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Penning
authors.forename: Albert
authors.initials: A
authors.lastname: Khilevich
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Chen
authors.forename: Mark A
authors.initials: MA
authors.lastname: Russell
authors.forename: Mark L
authors.initials: ML
authors.lastname: Boys
authors.forename: Yaping
authors.initials: Y
authors.lastname: Wang
authors.forename: Tiffany
authors.initials: T
authors.lastname: Duffin
authors.forename: V Wayne
authors.initials: VW
authors.lastname: Engleman
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Finn
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Freeman
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Hanneke
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Keene
authors.forename: Jon A
authors.initials: JA
authors.lastname: Klover
authors.forename: G Allen
authors.initials: GA
authors.lastname: Nickols
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Nickols
authors.forename: Randall K
authors.initials: RK
authors.lastname: Rader
authors.forename: Steven L
authors.initials: SL
authors.lastname: Settle
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Shannon
authors.forename: Christina N
authors.initials: CN
authors.lastname: Steininger
authors.forename: Marisa M
authors.initials: MM
authors.lastname: Westlin
authors.forename: William F
authors.initials: WF
authors.lastname: Westlin
mesh_terms: 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
chemical_list: D039302:Integrin alphaVbeta3; D007555:Isoxazoles; D011720:Pyrazoles; C031280:pyrazole