Design, synthesis and biological evaluation of non-hydrolyzable phosphate mimetics of receptor subtype selective LPA antagonists

Lysophosphatidic acid (LPA) is an endogenous lysophospholipid that is generated by a variety of cell types. It is thought to be responsible for eliciting numerous biological responses of significant importance. These include wound healing, cancer progression, atherogenesis and neoplasia. LPA causes its biological effects by acting upon a family of G-coupled protein receptors (GPCRs) formerly known as Endotheilial differentiation gene (Edg) receptors. These receptors are now referred to as simply LPA receptors. There are currently 4 extracellular LPA receptors which include LPA1 (formerly Edg2), LPA2 (formerly Edg4), LPA3 (formerly Edg7) and LPA 4 that was recently de-orphaned (formerly GPR23) and one intracellular receptor PPARgamma. Recently we have described a subtype selective antagonist for the LPA1 and LPA3 receptors based on the N-acyl ethanol amide phosphoric acid (NAEPA) moiety. This work describes the synthetic efforts used to make non-hydrolyzable alpha and beta substituted phosphonate analogs of NAEPA; as well as carboxylic acid analogs of NAEPA. The structure activity relationship profile of these unique compounds will also be discussed.