R-isomers of Arg-Gly-Asp (RGD) mimics as potent alphavbeta3 inhibitors.
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.
Nagarajan
Srinivasan R
SR
Pfizer Global Research and Development, St. Louis Laboratories, Pfizer Inc., 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA. Srinivasan.Nagarajan@Pfizer.com
Devadas
Balekudru
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Malecha
James W
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Hwang-Fun
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Ruminski
Peter G
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Rico
Joseph G
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Rogers
Thomas E
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Laura D
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Joe T
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Kleine
H Peter
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Lantz
Melissa K
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Green
Nawasa F
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Russell
Mark A
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Bryan H
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Miller
Lawrence M
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Meyer
Debra M
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Duffin
Tiffany D
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Engleman
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Finn
Mary B
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Sandra K
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Griggs
David W
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Williams
Melanie L
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Maureen A
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Jodi A
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Kristen E
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Steininger
Christina
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Westlin
Marisa M
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Keene
Jeffery L
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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
D000596:Amino Acids; D000970:Antineoplastic Agents; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid