Four years ago we proposed an integrated program of synthetic chemistry and molecular pharmacology with the goals of gaining a better understanding of the structure activity relationships (SAR) in lysophosphatidic acid (LPA) and discovering LPA receptor selective agonists and antagonists. We have achieved this goal, as well as the goal of defining these compounds at recombinant LPA receptors and lipid phosphate phosphohydrolases (LPP). Our collaborators have shown that our lead LPA receptor antagonist is efficacious in several animal models. Further, we exceeded the goals by our discovery of synthetic compounds active at individual sphingosine 1-phosphate (S1P) receptors. ? ? Our present Aims can be stated succinctly as: (1) Developing further the SAR of LPA mediators whereby we will define the pharmacophore systems responsible for the agonist and antagonist activities at individual LPA receptors; (2) Profiling our synthetic compounds for inhibition of LPA metabolic enzymes and (3) Using our compounds to discover new lysophospholipid receptors. ? ? The strength of our program remains the combination of synthetic chemistry and molecular pharmacology - an interaction strengthened by the molecular definition of target proteins including the LPA receptors, lysophospholipase D and lipid phosphohydrolases. Minimally, our efforts will extend significantly the SAR for receptors, phosphatases and synthetic enzymes and optimize the existing lead antagonist and enzyme inhibitor structures. Optimally, we will discover new classes of LPA receptor antagonists and agonists, identify lysophospholipase D inhibitors and describe additional LPA receptors. Our work will enable a determination of the effects of blockage or mimicry of LPA signaling and thus provide crucial information as to what LPA signaling pathways might be valid targets for therapeutic intervention. ? ? ?
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