title: Discovery of +(2-{4-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy]phenyl}-cyclopropyl)acetic acid as potent and selective alphavbeta3 inhibitor: design, synthesis, and optimization.
abstract: The integrin alpha(v)beta(3) is expressed in a number of cell types and is thought to play a major role in several pathological conditions. Various small molecules that inhibit the integrin have been shown to suppress tumor growth and retinal angiogenesis. The tripeptide Arg-Gly-Asp (RGD), a common binding motif in several ligands that bind to alpha(v)beta(3), has been depeptidized and optimized in our efforts toward discovering a small molecule inhibitor. We recently disclosed the synthesis and biological activity of several small molecules that did not contain any peptide bond and mimic the tripeptide RGD. The phenethyl group in one of the lead compounds was successfully replaced with a cyclopropyl moiety. The new lead compound was optimized for potency, selectivity, and for its ADME properties. We describe herein the discovery, synthesis, and optimization of cyclopropyl containing analogs that are potent and selective inhibitors of alpha(v)beta(3).
authors: Pfizer Global Research and Development, St. Louis Laboratories, Pfizer, Inc., 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA. Srinivasan.Nagarajan@Pfizer.com
authors: Srinivasan R
authors: SR
authors: Nagarajan
authors: Hwang-Fun
authors: HF
authors: Lu
authors: Alan F
authors: AF
authors: Gasiecki
authors: Ish K
authors: IK
authors: Khanna
authors: Mihir D
authors: MD
authors: Parikh
authors: Bipinchandra N
authors: BN
authors: Desai
authors: Thomas E
authors: TE
authors: Rogers
authors: Michael
authors: M
authors: Clare
authors: Barbara B
authors: BB
authors: Chen
authors: Mark A
authors: MA
authors: Russell
authors: Jeffery L
authors: JL
authors: Keene
authors: Tiffany
authors: T
authors: Duffin
authors: V Wayne
authors: VW
authors: Engleman
authors: Mary B
authors: MB
authors: Finn
authors: Sandra K
authors: SK
authors: Freeman
authors: Jon A
authors: JA
authors: Klover
authors: G Alan
authors: GA
authors: Nickols
authors: Maureen A
authors: MA
authors: Nickols
authors: Kristen E
authors: KE
authors: Shannon
authors: Christina A
authors: CA
authors: Steininger
authors: William F
authors: WF
authors: Westlin
authors: Marisa M
authors: MM
authors: Westlin
authors: Melanie L
authors: ML
authors: Williams
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D019540:Area Under Curve; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D015195:Drug Design; D006207:Half-Life; D006801:Humans; D007202:Indicators and Reagents; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: C520657:2-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxyphenyl)-cyclopropyl)acetic acid; D000085:Acetates; D007202:Indicators and Reagents; D039302:Integrin alphaVbeta3; D009287:Naphthyridines