Pharmacokinetic and pharmacodynamic characterization of an oral lysophosphatidic acid type 1 receptor-selective antagonist

Lysophosphatidic acid (LPA) is a bioactive phospholipid that signals through a family of at least six G protein-coupled receptors designated LPA₁₋₆. LPA type 1 receptor (LPA₁) exhibits widespread tissue distribution and regulates a variety of physiological and pathological cellular functions. Here,...

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Published in:	The Journal of pharmacology and experimental therapeutics Vol. 336; no. 3; p. 693
Main Authors:	Swaney, J S, Chapman, C, Correa, L D, Stebbins, K J, Broadhead, A R, Bain, G, Santini, A M, Darlington, J, King, C D, Baccei, C S, Lee, C, Parr, T A, Roppe, J R, Seiders, T J, Ziff, J, Prasit, P, Hutchinson, J H, Evans, J F, Lorrain, D S
Format:	Journal Article
Language:	English
Published:	United States 01-03-2011
Subjects:	Administration, Oral Animals Antifibrinolytic Agents - administration & dosage Antifibrinolytic Agents - chemistry Antifibrinolytic Agents - pharmacokinetics Cell Line, Tumor CHO Cells Cricetinae Cricetulus Dogs Humans Male Mice Protein Binding - physiology Rats Rats, Sprague-Dawley Receptors, Lysophosphatidic Acid - antagonists & inhibitors Receptors, Lysophosphatidic Acid - metabolism
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Summary:	Lysophosphatidic acid (LPA) is a bioactive phospholipid that signals through a family of at least six G protein-coupled receptors designated LPA₁₋₆. LPA type 1 receptor (LPA₁) 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 LPA₁-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 LPA₁ receptor antagonist because it inhibited GTPγS binding to Chinese hamster ovary (CHO) cell membranes overexpressing recombinant human or mouse LPA₁ with IC₅₀ values of 0.98 and 0.73 μM, respectively, and exhibited no LPA₁ agonism. In functional assays, AM095 inhibited LPA-driven chemotaxis of CHO cells overexpressing mouse LPA₁ (IC₅₀= 778 nM) and human A2058 melanoma cells (IC₅₀ = 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 LPA₁ receptor antagonist with good oral exposure and antifibrotic activity in rodent models.
ISSN:	1521-0103
DOI:	10.1124/jpet.110.175901