Novel Antagonist of the Type 2 Lysophosphatidic Acid Receptor (LPA2), UCM-14216, Ameliorates Spinal Cord Injury in Mice

Nora Khiar-Fernández, Debora Zian, Henar Vázquez-Villa, R. Fernando Martínez, Andrea Escobar-Peña, Román Foronda-Sainz, Manisha Ray, Maria Puigdomenech-Poch, Giovanni Cincilla, Melchor Sánchez-Martínez, Yasuyuki Kihara, Jerold Chun, Rubèn López-Vales, María L. López-Rodríguez*, Silvia Ortega-Gutiérrez

*Autor corresponent d’aquest treball

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Resum

Spinal cord injuries (SCIs) irreversibly disrupt spinal connectivity, leading to permanent neurological disabilities. Current medical treatments for reducing the secondary damage that follows the initial injury are limited to surgical decompression and anti-inflammatory drugs, so there is a pressing need for new therapeutic strategies. Inhibition of the type 2 lysophosphatidic acid receptor (LPA2) has recently emerged as a new potential pharmacological approach to decrease SCI-associated damage. Toward validating this receptor as a target in SCI, we have developed a new series of LPA2antagonists, among which compound 54 (UCM-14216) stands out as a potent and selective LPA2receptor antagonist (Emax= 90%, IC50= 1.9 μM, KD= 1.3 nM; inactive at LPA1,3-6receptors). This compound shows efficacy in an in vivo mouse model of SCI in an LPA2-dependent manner, confirming the potential of LPA2inhibition for providing a new alternative for treating SCI.

Idioma originalEnglish
Pàgines (de-a)10956-10974
Nombre de pàgines19
RevistaJournal of Medicinal Chemistry
Volum65
Número16
DOIs
Estat de la publicacióPublicada - 10 d’ag. 2022

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