生物活性

• 靶点

  LPA Receptor 1 Ki:0.34μM

  LPA Receptor 3 Ki:0.93μM

  LPA Receptor 2 Ki:6.5μM

• 描述LPA (lysophosphatidic acid), which has been shown to be involved in certain diseases such as atherosclerosis and cancer, can act through its receptor like LPA receptor 1, LPA receptor 2, or LPA receptor 3 and elicit different biological actions, like Ca²⁺ mobilization, changing in cAMP accumulation, changing cell shape and motility, and cell proliferation. Ki16425 is a LPA receptor antagonist with Ki values of 0.34μM for mouse LPA receptor 1 and 0.93μM for human LPA receptor 3, but with much higher Ki value for human LPA receptor 2 (Ki=6.5μM). Pre-treatment with 1μM Ki16425 can inhibit LPA-induced [Ca2²⁺]_i increase in THP-1 cells and 3T3 fibroblasts. Also, Ki16425 could decrease the This LPA-induced response of inositol phosphate production in 3T3 fibroblasts and A431 cells, but not S1P3- or S1P2-expressing CHO cells, at concentration of 10μM. The cAMP accumulation inhibited by LPA in FRTL-5 thyroid cells in a PTX-sensitive manner could be almost completely suppressed by 10μM Ki16425. Cell proliferation and migration induced by LPA in Swiss 3T3 fibroblasts could be inhibited dose-dependently by Ki16425. Treatment with Ki16425 at dose of 10mg/kg intradermally could improve dermal and lung fibrosis in a mouse model of bleomycin-induced murine scleroderma. Pre-treatment with 10μM for 30 minutes could completely block LPA-induced YAP/TAZ phosphorylation and inhibit Hippo signaling pathway in HEK293A cells.
• 作用机制Ki16425 can antagonize the binding of LPA to the receptor, thus competitively inhibiting LPA-induced GTP binding and LPA receptor binding to membrane fractions.^[1]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  CHOK1 cells	-	Function assay	-	Antagonist activity at human recombinant LPA1 receptor expressed in CHOK1 cells assessed as inhibition of lysophosphatidic acid-induced intracellular calcium influx, IC50=0.51 μM	17467986
  HEK293 cells	-	Function assay	5 mins	Antagonist activity at human LPA1 receptor expressed in HEK293 cells assessed as inhibition of LPA-induced AP-TGF-alpha release treated 5 mins before LPA addition measured after 60 mins	22658556
  human chem1 cells	-	Function assay	-	Antagonist activity at LPA1 expressed in human chem1 cells assessed as effect on intracellular calcium mobilization by FLIPR assay, IC50=0.046 μM	20056548

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• 动物研究
  剂量	Mice: 1 mg/kg, 10 mg/kg[2] (i.d.); 20 mg/kg[4] (i.p.); 5 mg/kg[5] (i.v.); 25 mg/kg, 50 mg/kg[5] (p.o.)
  给药途径	i.d., i.p., i.v., p.o.
  动物药代数据	Animal Mice[5] Dose 5 mg/kg (i.v.) 50 mg/kg (p.o.) Administration i.v. p.o. F 14.41% (p.o.) T1/2 0.49 h (i.v.) 0.98 h (p.o.) Tmax 0.08 h (i.v.) 0.25 h (p.o.) CL 6.66 l/h/kg (i.v.) Cmax 2960 μg/ml (i.v.) 1658 μg/ml (p.o.)

• 参考文献

• [1] Ohta H, Sato K, et al. Ki16425, a subtype-selective antagonist for EDG-family lysophosphatidic acid receptors. Mol Pharmacol. 2003 Oct;64(4):994-1005.

  [2] Ohashi T, Yamamoto T, et al. Antifibrotic effect of lysophosphatidic acid receptors LPA1 and LPA3 antagonist on experimental murine scleroderma induced by bleomycin. Exp Dermatol. 2015 Sep;24(9):698-702.

  [3] Yu FX, Zhao B, et al. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell. 2012 Aug 17;150(4):780-91.

  [4] Sánchez-Marín L, Ladrón de Guevara-Miranda D, et al. Systemic blockade of LPA1/3 lysophosphatidic acid receptors by ki16425 modulates the effects of ethanol on the brain and behavior. Neuropharmacology. 2018 May 1;133:189-201.

  [5] David M, Ribeiro J, et al. Targeting lysophosphatidic acid receptor type 1 with Debio 0719 inhibits spontaneous metastasis dissemination of breast cancer cells independently of cell proliferation and angiogenesis. Int J Oncol. 2012 Apr;40(4):1133-41.

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