title: R-isomers of Arg-Gly-Asp (RGD) mimics as potent alphavbeta3 inhibitors.
abstract: The integrin alpha(v)beta(3), vitronectin receptor, is expressed in a number of cell types and has been shown to mediate adhesion of osteoclasts to bone matrix, vascular smooth muscle cell migration, and angiogenesis. We recently disclosed the discovery of a tripeptide Arg-Gly-Asp (RGD) mimic, which has been shown to be a potent inhibitor of the integrin alpha(v)beta(3) and has excellent anti-angiogenic properties including its suppression of tumor growth in animal models. In other investigations involving RGD mimics, only compounds containing the S-isomers of the beta-amino acids have been shown to be potent. We were surprised to find the potencies of analogs containing enantiomerically pure S-isomers of beta-amino acids which were only marginally better than the corresponding racemic mixtures. We therefore synthesized RGD mimics containing R-isomers of beta-amino acids and found them to be relatively potent inhibitors of alpha(v)beta(3). One of the compounds was examined in tumor models in mice and has been shown to significantly reduce the rate of growth and the size of tumors.
authors.affiliation: Pfizer Global Research and Development, St. Louis Laboratories, Pfizer Inc., 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA. Srinivasan.Nagarajan@Pfizer.com
authors.forename: Srinivasan R
authors.initials: SR
authors.lastname: Nagarajan
authors.forename: Balekudru
authors.initials: B
authors.lastname: Devadas
authors.forename: James W
authors.initials: JW
authors.lastname: Malecha
authors.forename: Hwang-Fun
authors.initials: HF
authors.lastname: Lu
authors.forename: Peter G
authors.initials: PG
authors.lastname: Ruminski
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Rico
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Rogers
authors.forename: Laura D
authors.initials: LD
authors.lastname: Marrufo
authors.forename: Joe T
authors.initials: JT
authors.lastname: Collins
authors.forename: H Peter
authors.initials: HP
authors.lastname: Kleine
authors.forename: Melissa K
authors.initials: MK
authors.lastname: Lantz
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.forename: Nawasa F
authors.initials: NF
authors.lastname: Green
authors.forename: Mark A
authors.initials: MA
authors.lastname: Russell
authors.forename: Bryan H
authors.initials: BH
authors.lastname: Landis
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Miller
authors.forename: Debra M
authors.initials: DM
authors.lastname: Meyer
authors.forename: Tiffany D
authors.initials: TD
authors.lastname: Duffin
authors.forename: V Wayne
authors.initials: VW
authors.lastname: Engleman
authors.forename: Mary B
authors.initials: MB
authors.lastname: Finn
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Freeman
authors.forename: David W
authors.initials: DW
authors.lastname: Griggs
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Williams
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Nickols
authors.forename: Jodi A
authors.initials: JA
authors.lastname: Pegg
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Shannon
authors.forename: Christina
authors.initials: C
authors.lastname: Steininger
authors.forename: Marisa M
authors.initials: MM
authors.lastname: Westlin
authors.forename: G Alan
authors.initials: GA
authors.lastname: Nickols
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Keene
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D003110:Colonic Neoplasms; D006934:Hypercalcemia / Q000139:chemically induced; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D007536:Isomerism; D008545:Melanoma; D051379:Mice; D008815:Mice, Inbred Strains; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D012878:Skin Neoplasms; D023041:Xenograft Model Antitumor Assays
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid