Phosphorothioate analogs of sn-2 radyl lysophosphatidic acid (LPA): Metabolically stabilized LPA receptor agonists |
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| Authors: | Guowei Jiang Asuka Inoue Junken Aoki Glenn D Prestwich |
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| Institution: | 1. Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, UT 84108-1257, United States;2. Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai 980-8578, Japan;3. Japan Science and Technology Agency, Core Research for Evolutional Sciences and Technology (CREST), Kawaguchi, Saitama 332-0012, Japan |
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| Abstract: | We describe an efficient synthesis of metabolically stabilized sn-2 radyl phosphorothioate analogs of lysophosphatidic acid (LPA), and the determination of the agonist activity of each analog for the six LPA receptors (LPA1–6) using a recently developed TGFα shedding assay. In general, the sn-2 radyl OMPT analogs showed similar agonist activities to the previous 1-oleoyl-2-O-methyl-glycerophosphothioate (sn-1 OMPT) analogs for LPA1–6 receptors. In most cases, the sn-2 radyl-OMPT analogs were more potent agonists than LPA itself. Most importantly, sn-2 alkyl OMPT analogs were very potent LPA5 and LPA6 agonists. The availability of sn-2 radyl OPMT analogs further refines the structure–activity relationships for ligand–receptor interactions for this class of GPCRs. |
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