Synonym
AM-966; AM 966; AM966.
IUPAC/Chemical Name
(R)-2-(4'-(4-(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)-3-methylisoxazol-5-yl)-[1,1'-biphenyl]-4-yl)acetic acid
InChi Key
WWQTWEWAPUCDDZ-QGZVFWFLSA-N
InChi Code
InChI=1S/C27H23ClN2O5/c1-16-25(29-27(33)34-17(2)22-5-3-4-6-23(22)28)26(35-30-16)21-13-11-20(12-14-21)19-9-7-18(8-10-19)15-24(31)32/h3-14,17H,15H2,1-2H3,(H,29,33)(H,31,32)/t17-/m1/s1
SMILES Code
O=C(O)CC1=CC=C(C2=CC=C(C3=C(NC(O[C@@H](C4=CC=CC=C4Cl)C)=O)C(C)=NO3)C=C2)C=C1
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, not in water
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
Biological target:
AM966 is a high affinity, selective, oral LPA1-antagonist, inhibits LPA-stimulated intracellular calcium release (IC50=17 nM).
In vitro activity:
Figures 1(a) and 1(b) show that AM966 rapidly reduces TEER in 15 min after treatment. The resistance returned to baseline within 2 h. This effect was similar to LPA treatment. The combination of LPA1 agonist (LPA) and antagonist (AM966) had no further reduction of TEER. These data suggest that both AM966 and LPA increase HLMVECs permeability and delays barrier integrity recovery time. As shown in Figures 1(c) and 1(d), AM966 reduces TEER in a concentration-dependent manner. The TEER recovered (0.1 and 1.0 μM AM966) within 2 h, while it remained in a low level with 10 μM AM966 stimulation. Further, this study examined the effect of AM966 on VE-cadherin expression on cell surface. As shown in Figure 1(e), VE-cadherin is primarily localized on cell-cell junctions. However, AM966 (1 μM, 30 min) causes paracellular gap formation and less VE-cadherin staining on cell-cell junctions. F-Actin staining shows that A966 increases stress fibers in HLMVECs (Figure 1(e)). Taken together with Figure 1, these data indicate that AM966 treatment leads to reduction of VE-cadherin expression on the cell-cell junction, increasing stress fibers, and gap formation, thus disrupting lung microvascular barrier integrity.
Reference: Mediators Inflamm. 2017; 2017: 6893560. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5350330/
In vivo activity:
Brain water content (BWC) and neurobehavior were assessed at 24 h and 72 h after ICH. ICH groups showed significantly worse outcomes in neurobehavioral tests than the sham-treated mice after 24 h (p < 0.05). Compared with vehicle group, neurobehavioral function significantly improved with AM966 treatment at a dose of 30 mg/kg and 90 mg/kg 24 h after ICH (p < 0.05, Fig. 2A–C). Compared with the vehicle group, BWC in the right basal ganglia and cortex were increased at 24 h (p < 0.05) and it was significantly reduced with the administration of AM966 (p < 0.05, Fig. 2D). These analyses revealed no significant differences between the two doses of AM966 (Fig. 2A–D). Therefore, this study chose the dose of 30 mg/kg AM966 for the remaining experiments and observed a similar pattern in neurobehavior and BWC evaluated 72 h post-ICH (p < 0.05, Fig. 2E–H). Additionally, the administration of 30 mg/kg AM966 at 4 h and 16 h after ICH significantly reduced BWC and improved neurobehavioral function compared to vehicle group at 72 h after ICH (p < 0.05, Fig. 2I–L).
Reference: Brain Behav Immun. 2021 Jan;91:615-626. https://pubmed.ncbi.nlm.nih.gov/33035633/
|
Solvent |
mg/mL |
mM |
comments |
| Solubility |
| DMSO |
65.0 |
132.40 |
|
| DMSO:PBS (pH 7.2) (1:4) |
0.2 |
0.41 |
|
| DMF |
30.0 |
61.11 |
|
| Ethanol |
2.5 |
5.09 |
|
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
490.93
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
Formulation protocol:
1. Cai J, Wei J, Li S, Suber T, Zhao J. AM966, an Antagonist of Lysophosphatidic Acid Receptor 1, Increases Lung Microvascular Endothelial Permeability through Activation of Rho Signaling Pathway and Phosphorylation of VE-Cadherin. Mediators Inflamm. 2017;2017:6893560. doi: 10.1155/2017/6893560. Epub 2017 Feb 27. PMID: 28348461; PMCID: PMC5350330.
2. Olianas MC, Dedoni S, Onali P. LPA1 Mediates Antidepressant-Induced ERK1/2 Signaling and Protection from Oxidative Stress in Glial Cells. J Pharmacol Exp Ther. 2016 Nov;359(2):340-353. doi: 10.1124/jpet.116.236455. Epub 2016 Sep 7. PMID: 27605627.
3. Gao L, Shi H, Sherchan P, Tang H, Peng L, Xie S, Liu R, Hu X, Tang J, Xia Y, Zhang JH. Inhibition of lysophosphatidic acid receptor 1 attenuates neuroinflammation via PGE2/EP2/NOX2 signalling and improves the outcome of intracerebral haemorrhage in mice. Brain Behav Immun. 2021 Jan;91:615-626. doi: 10.1016/j.bbi.2020.09.032. Epub 2020 Oct 6. PMID: 33035633.
4. Ueda H, Neyama H, Matsushita Y. Lysophosphatidic Acid Receptor 1- and 3-Mediated Hyperalgesia and Hypoalgesia in Diabetic Neuropathic Pain Models in Mice. Cells. 2020 Aug 16;9(8):1906. doi: 10.3390/cells9081906. PMID: 32824296; PMCID: PMC7465054.
In vitro protocol:
1. Cai J, Wei J, Li S, Suber T, Zhao J. AM966, an Antagonist of Lysophosphatidic Acid Receptor 1, Increases Lung Microvascular Endothelial Permeability through Activation of Rho Signaling Pathway and Phosphorylation of VE-Cadherin. Mediators Inflamm. 2017;2017:6893560. doi: 10.1155/2017/6893560. Epub 2017 Feb 27. PMID: 28348461; PMCID: PMC5350330.
2. Olianas MC, Dedoni S, Onali P. LPA1 Mediates Antidepressant-Induced ERK1/2 Signaling and Protection from Oxidative Stress in Glial Cells. J Pharmacol Exp Ther. 2016 Nov;359(2):340-353. doi: 10.1124/jpet.116.236455. Epub 2016 Sep 7. PMID: 27605627.
In vivo protocol:
1. Gao L, Shi H, Sherchan P, Tang H, Peng L, Xie S, Liu R, Hu X, Tang J, Xia Y, Zhang JH. Inhibition of lysophosphatidic acid receptor 1 attenuates neuroinflammation via PGE2/EP2/NOX2 signalling and improves the outcome of intracerebral haemorrhage in mice. Brain Behav Immun. 2021 Jan;91:615-626. doi: 10.1016/j.bbi.2020.09.032. Epub 2020 Oct 6. PMID: 33035633.
2. Ueda H, Neyama H, Matsushita Y. Lysophosphatidic Acid Receptor 1- and 3-Mediated Hyperalgesia and Hypoalgesia in Diabetic Neuropathic Pain Models in Mice. Cells. 2020 Aug 16;9(8):1906. doi: 10.3390/cells9081906. PMID: 32824296; PMCID: PMC7465054.
1: Ueda H, Neyama H, Matsushita Y. Lysophosphatidic Acid Receptor 1- and 3-Mediated Hyperalgesia and Hypoalgesia in Diabetic Neuropathic Pain Models in Mice. Cells. 2020 Aug 16;9(8):1906. doi: 10.3390/cells9081906. PMID: 32824296; PMCID: PMC7465054.
2: Cai J, Wei J, Li S, Suber T, Zhao J. AM966, an Antagonist of Lysophosphatidic Acid Receptor 1, Increases Lung Microvascular Endothelial Permeability through Activation of Rho Signaling Pathway and Phosphorylation of VE-Cadherin. Mediators Inflamm. 2017;2017:6893560. doi: 10.1155/2017/6893560. Epub 2017 Feb 27. PMID: 28348461; PMCID: PMC5350330.
3: Swaney JS, Chapman C, Correa LD, Stebbins KJ, Bundey RA, Prodanovich PC, Fagan P, Baccei CS, Santini AM, Hutchinson JH, Seiders TJ, Parr TA, Prasit P, Evans JF, Lorrain DS. A novel, orally active LPA(1) receptor antagonist inhibits lung fibrosis in the mouse bleomycin model. Br J Pharmacol. 2010 Aug;160(7):1699-713. doi: 10.1111/j.1476-5381.2010.00828.x. PMID: 20649573; PMCID: PMC2936842.
