AM966 is a potent, selective, orally bioavailable antagonist of the LPA1 receptor. It effectively inhibits LPA1-mediated chemotaxis in various cell types, including human A2058 melanoma cells (IC50=138±43 nM), IMR-90 human lung fibroblasts (IC50=182±86 nM), and CHO mLPA1 cells (IC50=469±54 nM) [1]. LPA-induced activation of ERK1/2 is entirely suppressed by AM966 (100 nM), which exhibits selective antagonism against LPA1 receptor over LPA2-5, with an IC50 value of 3.8±0.4 nM. Pretreatment with AM966 (100 nM) completely abolishes ERK1/2 phosphorylation induced by Mianserin [2].
体内研究
In a Bleomycin model lasting 3 days, AM966 (30 mg/kg, BID) mitigates vascular leakage, inflammation, and lung injury. Additionally, it inhibits lung fibrosis, maintains mouse body weight, and reduces lung inflammation 14 days post-Bleomycin lung injury. AM966 demonstrates superior efficacy compared to Pirfenidone in the 14-day Bleomycin model, reducing mortality and fibrosis at later time points following Bleomycin injury [1].
体外研究
AM966 is a potent, selective, orally bioavailable antagonist of the LPA1 receptor. It effectively inhibits LPA1-mediated chemotaxis in various cell types, including human A2058 melanoma cells (IC50=138±43 nM), IMR-90 human lung fibroblasts (IC50=182±86 nM), and CHO mLPA1 cells (IC50=469±54 nM) [1].
LPA-induced activation of ERK1/2 is entirely suppressed by AM966 (100 nM), which exhibits selective antagonism against LPA1 receptor over LPA2-5, with an IC50 value of 3.8±0.4 nM. Pretreatment with AM966 (100 nM) completely abolishes ERK1/2 phosphorylation induced by Mianserin [2].
作用机制
AM966 can antagonize LPA1 receptors and inhibit LPA-stimulated intracellular calcium release.[1]
AM966 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Human lung microvascular endothelial cells (HLMVECs)
0.1, 1.0, 10.0 µM
15 minutes to 2 hours
To investigate the effect of AM966 on the barrier function of HLMVECs. Results showed that AM966 rapidly decreased transendothelial electrical resistance (TEER), increased gap formation, and disrupted barrier integrity through activation of RhoA/Rho kinase pathway and phosphorylation of VE-cadherin.
Mediators Inflamm. 2017;2017:6893560.
M2 macrophages
100 nM
24 hours
Inhibited invasion and proliferation of JEG3 cells
Autophagy. 2022 Oct;18(10):2459-2480.
IMR-90 human lung fibroblasts
181 nM (IC50)
16-18 hours
To evaluate the inhibitory effect of AM966 on LPA-induced chemotaxis, results showed that AM966 effectively inhibited the chemotaxis of IMR-90 cells.
Br J Pharmacol. 2010 Aug;160(7):1699-713.
CHO cells stably expressing human LPA1 receptors
17 nM (IC50)
30 minutes
To evaluate the antagonistic effect of AM966 on human LPA1 receptors, results showed that AM966 effectively inhibited LPA-stimulated intracellular calcium release.
Br J Pharmacol. 2010 Aug;160(7):1699-713.
A549 human non-small cell lung cancer cells
1 µM
90 minutes
Blockade of LPA1 receptor, inhibiting PA-stimulated lung cancer cell migration
Biomedicines. 2023 Jun 23;11(7):1804.
AM966 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Female C57BL/6 mice
Bleomycin-induced lung fibrosis model
Oral gavage
10, 30, 60 mg/kg
Twice daily, for 3-28 days
To evaluate the efficacy of AM966 in the bleomycin-induced lung fibrosis model, results showed that AM966 reduced lung injury, vascular leakage, inflammation and fibrosis, and decreased the concentrations of multiple pro-fibrotic and pro-inflammatory cytokines in BALF.
Br J Pharmacol. 2010 Aug;160(7):1699-713.
CD1 mice
Intracerebral hemorrhage model
Oral
30 mg/kg
Administered at 1 and 12 hours post-ICH
AM966-mediated LPA1 suppression relieved PMN recruitment, diminished brain oedema, demonstrated extravasation (as evidenced by EBS), protected BBB integrity, and enhanced neurologic activity following ICH
Fluids Barriers CNS. 2023 May 10;20(1):33
Mice
C57Bl/6J male mice
Intraperitoneal injection
50 mg/kg
Single injection, measured after 30 minutes
LPA injection caused an ~50% fall in circulating GLP-1, which was completely prevented by LPAR1/3 antagonist Ki16425, LPAR1 antagonists AM095 and AM966. LPAR2 antagonist LPA2-antagonist 1 did not significantly restore GLP-1 levels.
Int J Mol Sci. 2022 Apr 9;23(8):4163.
Mice
C57 /Bl6 mice
Intraperitoneal injection
Low dose (22 mg/kg), medium dose (33 mg/kg), and high dose (43 mg/kg)
Every 24 hours for 3 days
To investigate the effect of LPAR1 blockade on gastrointestinal motility and ENS structure in mice. Results showed that AM966 significantly reduced gastrointestinal transit, leading to weight loss and ENS structural alterations, including neuronal loss and glial cell morphological changes.
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