Bioactive Synthetic Analogues of Lysophosphatidic Acid (LPA) for Cell Growth, Muscle Contraction, Platelet Aggregation, etc.
Over thirty new analogues of phosphatidic acid and lysophosphatidic acid (LPA) have been synthesized. Results show that some of these analogues can act as either agonists or antagonists for a variety of receptors, some act as inhibitors of lipid phosphatases, while some potentiate activities of native LPA ligands. Importantly, we have identified LPA analogues that are inactive on one receptor subtype but highly potent agonists for another subtype.
These compounds have significant potential as research reagents. They have greater potential value as leads for drug discovery and as tools for assay development to facilitate drug discovery and lead development. LPA is a ligand that is important in platelet aggregation, cell proliferation, and nuclear receptor activation. The key therapeutic applications are in the areas of cancer, inflammation, diabetes and wound repair.
Stage of Development
A PCT application has been filed and nationalized to the U.S. and Europe. It has the publication number WO 2004/092188.
Any or all of these analogs are available for further developmental research support and/or licensing under either exclusive or non-exclusive terms.
*Prestwich GD, Xu Y, Qian L, Gajewiak J, and Jiang G. New metabolically stabilized analogues of lysophosphatidic acid: agonists, antagonists and enzyme inhibitors. Biochemical Society Transactions 33(Part 6):1357-61(2005).
*Qian L, Xu Y, Hasegawa Y, Aoki J, Mills GB, and Prestwich GD. Enantioselective responses to a phosphorothioate analogue of lysophosphatidic acid with LPA3 receptor-selective agonist activity. Journal of Medical Chemistry 46(26):5575-78(2002).
*Xu Y and Prestwich GD. Synthesis of chiral (a,a-difluoroalkyl)phosphonate analogues of (lyso)phosphatidic acid via hydrolytic kinetic resolution. Organic Letters 4(23): 4021-24(2002).
*See also http://www.bioscience.utah.edu/mb/mbFaculty/prestwich/prestwich.html
Glenn Prestwich, Yong Xu, Lian Qian
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