Synthesis and Biological Evaluation of Lysophosphatidic Acid Analogues Using Conformational Restriction and...

Lysophosphatidic acid (LPA) is a key player in many physiological and pathophysiological processes. The biological activities of LPA are mediated through interactions with-at least-six subtypes of G-protein-coupled receptors (GPCRs) named LPA_1-6. Developing a pharmacological tool molecule that activates LPA subtype receptors selectively will allow a better understanding of their specific physiological roles. Here, we designed and synthesized conformationally restricted 25 1-oleoyl LPA analogues MZN-001 to MZN-025 by incorporating its glycerol linker into dihydropyran, tetrahydropyran, and pyrrolidine rings and variating the lipophilic chain. The agonistic activities of these compounds were evaluated using the TGFα shedding assay. Overall, the synthesized analogues exhibited significantly reduced agonistic activities toward LPA₁, LPA₂, and LPA₆, while demonstrating potent activities toward LPA₃, LPA₄, and LPA₅ compared to the parent LPA. Specifically, MZN-010 showed more than 10 times greater potency (EC₅₀ = 4.9 nM) than the standard 1-oleoyl LPA (EC₅₀ = 78 nM) toward LPA₅ while exhibiting significantly lower activity on LPA₁, LPA₂, and LPA₆ and comparable potency toward LPA₃ and LPA₄. Based on the MZN-010 scaffold, we synthesized additional analogues with improved selectivity and potency toward LPA₅. Compound MZN-021, which contains a saturated lipophilic chain, exhibited 50 times more potent activity (EC₅₀ = 1.2 nM) than the natural LPA against LPA₅ with over a 45-fold higher selectivity when compared to those of other LPA receptors. Thus, MZN-021 was found to be a potent and selective LPA₅ agonist. The findings of this study could contribute to broadening the current knowledge about the stereochemical and three-dimensional arrangement of LPA pharmacophore components inside LPA receptors and paving the way toward synthesizing other subtype-selective pharmacological probes.