TY - JOUR
T1 - Novel Antagonist of the Type 2 Lysophosphatidic Acid Receptor (LPA2), UCM-14216, Ameliorates Spinal Cord Injury in Mice
AU - Khiar-Fernández, Nora
AU - Zian, Debora
AU - Vázquez-Villa, Henar
AU - Martínez, R. Fernando
AU - Escobar-Peña, Andrea
AU - Foronda-Sainz, Román
AU - Ray, Manisha
AU - Puigdomenech-Poch, Maria
AU - Cincilla, Giovanni
AU - Sánchez-Martínez, Melchor
AU - Kihara, Yasuyuki
AU - Chun, Jerold
AU - López-Vales, Rubèn
AU - López-Rodríguez, María L.
AU - Ortega-Gutiérrez, Silvia
N1 - This work has been supported by the Spanish Ministerio de
Ciencia, Innovación y Universidades (PID2019-106279RB-I00
to M.L.L.-R. and S.O.-G., PID2020-120267RB-I00 to R.L.-V.,
predoctoral FPU grants to N.K.-F., D.Z., and A.E.-P., and Juan
de la Cierva postdoctoral fellowship to R.F.M.), Comunidad de
Madrid (PEJ Program) to R.F.-S., and grants from the National
Institute of Health (NIH) R01NS103940 (Y.K.) and
R01NS084398, R01MH051699 and Department of Defense
DOD W81XWH-17-1-0455 (J.C.). R.L.-V. is the recipient of
an ICREA Academia award.
PY - 2022/8/10
Y1 - 2022/8/10
N2 - 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.
AB - 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.
KW - Animals
KW - Mice
KW - Receptors, Lysophosphatidic Acid/antagonists & inhibitors
KW - Spinal Cord
KW - Spinal Cord Injuries/drug therapy
UR - http://www.scopus.com/inward/record.url?scp=85136259124&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.2c00046
DO - 10.1021/acs.jmedchem.2c00046
M3 - Article
C2 - 35948083
AN - SCOPUS:85136259124
SN - 0022-2623
VL - 65
SP - 10956
EP - 10974
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 16
ER -