AM095

AM095 is a novel, potent and orally bioavailable antagonist of lysophosphatidic acid type 1 receptor (LPA1) with IC50 values of 0.73 and 0.98 μM for mouse or recombinant human LPA1, respectively [1].

In vitro, AM095 has shown to inhibit LPA1-induced chemotaxis of both mouse LPA1/CHO cells and human A2058 melanoma cells with IC50 values of 0.78 μM and 0.23μM [1].

In vivo, AM095 could dose-dependently block LPA-induced histamine release with an ED50 value of 8.3 mg/kg in mice. Additionally, AM095 has been revealed to remarkably reduce the BALF collagen and protein with an ED50 value of 10 mg/kg in lungs. AM095 has also shown to decrease both macrophage and lymphocyte infiltration induced by bleomycin in mice [1].

References:
[1] Swaney JS1, Chapman C, Correa LD, Stebbins KJ, Broadhead AR, Bain G, Santini AM, Darlington J, King CD, Baccei CS, Lee C, Parr TA, Roppe JR, Seiders TJ, Ziff J, Prasit P, Hutchinson JH, Evans JF, Lorrain DS. Pharmacokinetic and pharmacodynamic characterization of an oral lysophosphatidic acid type 1 receptor-selective antagonist. J Pharmacol Exp Ther. 2011 Mar;336(3):693-700.

A549 cells as a model to study endogenous LPA1 receptor signaling and regulation.[Pubmed:28943105]

Eur J Pharmacol. 2017 Nov 15;815:258-265.

Lysophosphatidic acid (LPA) modulates the function of many organs, including the lung. A549 is a lung carcinoma-derived cell line, frequently used as a model for type II pneumocytes. Here we show that these cells expressed messenger RNA coding for LPA1-3 receptors with the following order of abundance: LPA1 > LPA2 > LPA3 and that LPA was able to increase intracellular calcium, extracellular signal-regulated kinases 1/2 phosphorylation, and cell contraction. These effects were blocked by Ki16425, an antagonist selective for LPA1 and LPA3 receptors, and by the LPA1-selective antagonist, AM095. Activation of protein kinase C inhibited LPA-induced intracellular calcium increase. This action was blocked by protein kinase C inhibitors and enzyme down-regulation. Phorbol myristate acetate and AM095, but not Ki16425, decreased the baseline intracellular calcium concentration. Ki16425 blocked the effect of AM095 but not that of phorbol myristate acetate. The data indicate that LPA1 receptors exhibit constitutive activity and that AM095 behaves as an inverse agonist, whereas Ki16425 appears to be a classic antagonist. Furthermore, the LPA agonist, 1-oleoyl-2-O-methyl-rac-glycerophosphothionate, OMPT, induced a weak increase in intracellular calcium, but was able to induce full ERK 1/2 phosphorylation and cell contraction. These effects were blocked by AM095. These data suggest that OMPT is a biased LPA1 agonist. A549 cells express functional LPA1 receptors and seem to be a suitable model to study their signaling and regulation.

Amelioration of dermal fibrosis by genetic deletion or pharmacologic antagonism of lysophosphatidic acid receptor 1 in a mouse model of scleroderma.[Pubmed:21305523]

Arthritis Rheum. 2011 May;63(5):1405-15.

OBJECTIVE: Scleroderma (systemic sclerosis [SSc]), is characterized by progressive multiorgan fibrosis. We recently implicated lysophosphatidic acid (LPA) in the pathogenesis of pulmonary fibrosis. The purpose of the present study was to investigate the roles of LPA and two of its receptors, LPA(1) and LPA(2), in dermal fibrosis in a mouse model of SSc. METHODS: Wild type (WT), and LPA(1)-knockout (KO) and LPA(2)-KO mice were injected subcutaneously with bleomycin or phosphate buffered saline (PBS) once daily for 28 days. Dermal thickness, collagen content, and numbers of cells positive for alpha-smooth muscle actin (alpha-SMA) or phospho-Smad2 were determined in bleomycin-injected and PBS-injected skin. In separate experiments, a novel selective LPA(1) antagonist AM095 or vehicle alone was administered by oral gavage to C57BL/6 mice that were challenged with 28 daily injections of bleomycin or PBS. AM095 or vehicle treatments were initiated concurrently with, or 7 or 14 days after, the initiation of bleomycin and PBS injections and continued to the end of the experiments. Dermal thickness and collagen content were determined in injected skin. RESULTS: The LPA(1) -KO mice were markedly resistant to bleomycin-induced increases in dermal thickness and collagen content, whereas the LPA(2)-KO mice were as susceptible as the WT mice. Bleomycin-induced increases in dermal alpha-SMA+ and phospho-Smad2+ cells were abrogated in LPA(1)-KO mice. Pharmacologic antagonism of LPA(1) with AM095 significantly attenuated bleomycin-induced dermal fibrosis when administered according to either a preventive regimen or two therapeutic regimens. CONCLUSION: These results suggest that LPA/LPA(1) pathway inhibition has the potential to be an effective new therapeutic strategy for SSc, and that LPA(1) is an attractive pharmacologic target in dermal fibrosis.

Intercellular Lipid Mediators and GPCR Drug Discovery.[Pubmed:24404331]

Biomol Ther (Seoul). 2013 Nov;21(6):411-22.

G-protein-coupled receptors (GPCR) are the largest superfamily of receptors responsible for signaling between cells and tissues, and because they play important physiological roles in homeostasis, they are major drug targets. New technologies have been developed for the identification of new ligands, new GPCR functions, and for drug discovery purposes. In particular, intercellular lipid mediators, such as, lysophosphatidic acid and sphingosine 1-phosphate have attracted much attention for drug discovery and this has resulted in the development of fingolimod (FTY-720) and AM095. The discovery of new intercellular lipid mediators and their GPCRs are discussed from the perspective of drug development. Lipid GPCRs for lysophospholipids, including lysophosphatidylserine, lysophosphatidylinositol, lysophosphatidylcholine, free fatty acids, fatty acid derivatives, and other lipid mediators are reviewed.

Pharmacokinetic and pharmacodynamic characterization of an oral lysophosphatidic acid type 1 receptor-selective antagonist.[Pubmed:21159750]

J Pharmacol Exp Ther. 2011 Mar;336(3):693-700.

Lysophosphatidic acid (LPA) is a bioactive phospholipid that signals through a family of at least six G protein-coupled receptors designated LPA(1)(-)(6). LPA type 1 receptor (LPA(1)) exhibits widespread tissue distribution and regulates a variety of physiological and pathological cellular functions. Here, we evaluated the in vitro pharmacology, pharmacokinetic, and pharmacodynamic properties of the LPA(1)-selective antagonist AM095 (sodium, {4'-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}- acetate) and assessed the effects of AM095 in rodent models of lung and kidney fibrosis and dermal wound healing. In vitro, AM095 was a potent LPA(1) receptor antagonist because it inhibited GTPgammaS binding to Chinese hamster ovary (CHO) cell membranes overexpressing recombinant human or mouse LPA(1) with IC(5)(0) values of 0.98 and 0.73 muM, respectively, and exhibited no LPA(1) agonism. In functional assays, AM095 inhibited LPA-driven chemotaxis of CHO cells overexpressing mouse LPA(1) (IC(5)(0)= 778 nM) and human A2058 melanoma cells (IC(5)(0) = 233 nM). In vivo, we demonstrated that AM095: 1) had high oral bioavailability and a moderate half-life and was well tolerated at the doses tested in rats and dogs after oral and intravenous dosing, 2) dose-dependently reduced LPA-stimulated histamine release, 3) attenuated bleomycin-induced increases in collagen, protein, and inflammatory cell infiltration in bronchalveolar lavage fluid, and 4) decreased kidney fibrosis in a mouse unilateral ureteral obstruction model. Despite its antifibrotic activity, AM095 had no effect on normal wound healing after incisional and excisional wounding in rats. These data demonstrate that AM095 is an LPA(1) receptor antagonist with good oral exposure and antifibrotic activity in rodent models.

AM095 is a selective LPA1 receptor antagonist. The IC50 for AM095 antagonism of LPA-induced calcium flux of human or mouse LPA1-transfected CHO cells is 0.025 and 0.023 μM, respectively.

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