3-[({4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]phenyl}methyl)sulfanyl]propanoic acid

• ChemBase ID: 72621
• Molecular Formular: C23H23ClN2O5S
• Molecular Mass: 474.95712
• Monoisotopic Mass: 474.10162053
• SMILES: c1cccc(c1Cl)C(C)OC(=O)Nc1c(noc1c1ccc(cc1)CSCCC(=O)O)C
• Canonical SMILES: OC(=O)CCSCc1ccc(cc1)c1onc(c1NC(=O)OC(c1ccccc1Cl)C)C
• InChI: InChI=1S/C23H23ClN2O5S/c1-14-21(25-23(29)30-15(2)18-5-3-4-6-19(18)24)22(31-26-14)17-9-7-16(8-10-17)13-32-12-11-20(27)28/h3-10,15H,11-13H2,1-2H3,(H,25,29)(H,27,28)
• InChIKey: LLIFMNUXGDHTRO-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 3-[({4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]phenyl}methyl)sulfanyl]propanoic acid
• IUPAC Traditional name: 3-[({4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]phenyl}methyl)sulfanyl]propanoic acid
• Synonyms: Ki16425

Database IDs

• CAS Number: 355025-24-0
• PubChem SID: 162037546
• PubChem CID: 10367662

CALCULATED PROPERTIES

• Acid pKa: 4.5883265
• H Acceptors: 5
• H Donor: 2
• LogD (pH = 5.5): 4.1598372
• LogD (pH = 7.4): 2.3844004
• Log P: 5.120729
• Molar Refractivity: 125.7567 cm^3
• Polarizability: 48.861443 Å^3
• Polar Surface Area: 101.66 Å^2
• Rotatable Bonds: 10
• Lipinski's Rule of Five: false

PROPERTIES

Physical Property

• Solubility: DMSO

Safety Information

• Storage Condition: -20°C

Pharmacology Properties

• Target: LPA receptor

Product Information

• Salt Data: Free Base

DETAILS

Selleck Chemicals - S1315

Research Area

• Description: Cancer

Biological Activity

• Description: Ki16425 is a competitive, potent and reversible antagonist to LPA1, LPA2 and LPA3 with K_i of 0.34 μM, 6.5 μM and 0.93 μM, respectively.
• Targets: LPA1; LPA2; LPA3
• IC50: 0.34 μM (K_i); 6.5 μM (K_i); 0.93 μM (K_i)
• In Vitro: Kil6425 preferentially inhibits LPA1- and LPA3-mediated responses but has only a moderate effect on LPA2. Ki16425 inhibits the LPA-induced Ca(2+) response in THP-1 cells, 3T3 fibroblasts, and A431 cells, but had only a marginal effect in PC-12 cells and HL-60 cells, which means that Ki16425 seems to be a useful tool for evaluating the involvement of specific LPA receptors in the short-term response to LPA. Ki16425 inhibits long-term DNA synthesis and cell migration as induced by LPA in Swiss 3T3 fibroblasts. ^[1] Ki16425 reduces the LPA-induced activation of p42/p44 mitogen activated protein kinase (MAPK), while acting as a weak stimulator of p42/p44 MAPK on its own, properties typical of a protean agonist. Ki16425 also significantly reduces the NGF-induced stimulation of p42/p44 MAPK and inhibited NGF-stimulated neurite outgrowth in PC-12 cells. ^[2] Ki16425 markedly inhibits the expressions of COX-2 protein induced by synovial fluids. The enhancement of the IL-1 action by LPA on COX-2 expression is also inhibited by Ki16425. ^[3]
• In Vivo: Ki-16425 (30 mg/kg, i.p.) completely blocks LPA-induced neuropathic pain-like behaviors, when administered 30 min but not 90 min before lysophosphatidic acid injection, suggesting that Ki-16425 is a short-lived inhibitor. Ki-16425 also inhibits nerve injury-induced up-regulation of Caα2δ-1 in the dorsal root ganglion and reduction of SP immunoreactivity in the spinal dorsal horn. ^[4]

Protocol

• Protocol: Kinase Assay ^[1]
• Inositol Phosphate Production.: RH7777 cells are incubated for 1 min with or without Ki16425, and the inositol phosphates (sum of inositol bisphosphate and inositol trisphosphate) are measured. The results are normalized to 105 dpm of the total radioactivity incorporated into the cellular inositol lipids, and the radioactivity of trichloroacetic acid (5%)-insoluble fraction is considered as the total radioactivity. The Ki values for Ki16425 is estimated from inositol phosphate responses or Ca2+ responses, based on the following equation: Ki = (EC50 × B)/(EC50′ - EC50), where B is the concentration of Ki16425, and EC50 and EC50′ are the half-maximal effective concentration of LPA in the absence and presence of Ki16425. The half-maximal effective concentration is estimated as a value that graphically gives a 50% maximal response. With regard to the Schild regressions, the half-maximal effective concentration is estimated from the Scatchard plots. The Ki value is determined by plotting the log of Dose Ratio-1 at each concentration of Ki16425 against the log concentration of Ki16425. The x-intercept of the linear transformation equals the inverse log of the Ki.
• Protocol: Animal Study ^[4]
• Animal Models: Male standard ddY-strain mice are used.
• Formulation: Dissolved in sesame oil just before administration.
• Doses: 30 mg/kg.
• Administration: Administered via i.p.

References

• References: [1] Ohta H, et al, Mol Pharmacol, 2003, 64(4), 994-1005.
• References: [2] Moughal NA, et al. J Neurochem, 2006, 98(6), 1920-1929.
• References: [3] Nochi H, et al. J Immunol, 2008, 181(7), 5111-5119.
• References: [4] Ma L, et al. J Neurochem, 2009, 109(2), 603-610.

REFERENCES

• Moughal NA, et al. J Neurochem, 2006, 98(6), 1920-1929.
• Nochi H, et al. J Immunol, 2008, 181(7), 5111-5119.
• Ma L, et al. J Neurochem, 2009, 109(2), 603-610.
• Ohta H, et al, Mol Pharmacol, 2003, 64(4), 994-1005.