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

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Khiar Fernández, Nora and Zian, Debora and Vázquez Villa, Henar and Martínez, R. Fernando and Escobar Peña, Andrea and Foronda Sainz, Román and Ray, Manisha and Puigdomenech Poch, Maria and Cincilla, Giovanni and Sánchez Martínez, Melchor and Kihara, Yasuyuki and Chun, Jerold and López Vales, Rubèn and López Rodríguez, María L. and Ortega Gutiérrez, Silvia (2022) Novel Antagonist of the Type 2 Lysophosphatidic Acid Receptor (LPA2), UCM-14216, Ameliorates Spinal Cord Injury in Mice. Journal of Medicinal Chemistry . ISSN 0022-2623

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Official URL: https://doi.org/10.1021/acs.jmedchem.2c00046



Abstract

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 SCIassociated damage. Toward validating this receptor as a target in SCI, we have developed a new series of LPA2 antagonists, among which compound 54 (UCM14216) stands out as a potent and selective LPA2 receptor antagonist (Emax = 90%, IC50 = 1.9 μM, KD = 1.3 nM; inactive at LPA1,3−6 receptors). This compound shows efficacy in an in vivo mouse model of SCI in an LPA2-dependent manner, confirming the potential of LPA2 inhibition for providing a new alternative for treating SCI.


Item Type:Article
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CRUE-CSIC (Acuerdos Transformativos 2022)

Subjects:Sciences > Chemistry > Chemistry, Organic
Medical sciences > Medicine > Neurosciences
ID Code:74179
Deposited On:23 Aug 2022 11:10
Last Modified:23 Aug 2022 11:18

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