Design, synthesis and evaluation of subtype-selective and non-hydrolyzable lysophosphatidic acid receptor agonists and antagonists.

摘要

Lysophosphatidic acid (LPA, 1- or 2-O-acyl- sn-glycero-3-phosphate) is an endogenous glycerophospholipid that can be generated by many cell types to elicit various mitogenic and motogenic cellular responses of significant (patho)physiological relevance to processes including wound healing, atherogenesis and neoplasia. G-protein coupled receptors (GPCRs) of the endothelial differentiation gene (Edg) family transduce many of the biological effects of LPA. Despite potential applications of LPA receptor antagonists as therapeutic agents, the detailed ramifications of blockade of individual LPA receptors are largely unknown because subtype-selective and phosphatase-resistant antagonists are unavailable currently. Herein, we describe detailed structure-activity relationships (SARs) of LPA/Edg receptor agonists and antagonists, encompassing lead discovery, first and second generation lead optimization (with regard to potency/selectivity) and metabolic considerations. In doing so, we have adapted the chemistry of amino aldehyde olefination and homologation, diastereoselective carbonyl additions and N -heterocycle assembly and functionalization to phospholipid synthesis. These efforts have culminated in the discovery of the first non-hydrolyzable and LPA3 receptor-selective high-affinity antagonist reported to date. Moreover, we have begun to elucidate the receptor-specific (patho)physiological consequences of LPA signaling by pharmacologic implementation of our novel and subtype-selective LPA receptor antagonists in vitro and in intact animals.