Document Report Card

ID: ALA4610001

Journal: J Med Chem

Title: A Novel Agonist of the Type 1 Lysophosphatidic Acid Receptor (LPA₁), UCM-05194, Shows Efficacy in Neuropathic Pain Amelioration.

Authors: González-Gil I, Zian D, Vázquez-Villa H, Hernández-Torres G, Martínez RF, Khiar-Fernández N, Rivera R, Kihara Y, Devesa I, Mathivanan S, Del Valle CR, Zambrana-Infantes E, Puigdomenech M, Cincilla G, Sanchez-Martinez M, Rodríguez de Fonseca F, Ferrer-Montiel AV, Chun J, López-Vales R, López-Rodríguez ML, Ortega-Gutiérrez S.

Abstract: Neuropathic pain (NP) is a complex chronic pain state with a prevalence of almost 10% in the general population. Pharmacological options for NP are limited and weakly effective, so there is a need to develop more efficacious NP attenuating drugs. Activation of the type 1 lysophosphatidic acid (LPA₁) receptor is a crucial factor in the initiation of NP. Hence, it is conceivable that a functional antagonism strategy could lead to NP mitigation. Here we describe a new series of LPA₁ agonists among which derivative (S)-17 (UCM-05194) stands out as the most potent and selective LPA₁ receptor agonist described so far (E_max = 118%, EC₅₀ = 0.24 μM, K_D = 19.6 nM; inactive at autotaxin and LPA_2-6 receptors). This compound induces characteristic LPA₁-mediated cellular effects and prompts the internalization of the receptor leading to its functional inactivation in primary sensory neurons and to an efficacious attenuation of the pain perception in an in vivo model of NP.

CiteXplore: 31790581

DOI: 10.1021/acs.jmedchem.9b01287