Abstract
The alpha4beta1 integrin (very late antigen-4, VLA-4) plays an important role in the migration of lymphocytes, monocytes, and eosinophils, but not neutrophils, to sites of inflammation. Pharmacological antagonism of VLA-4 is an attractive prospect for the treatment of predominantly eosinophil mediated diseases such as asthma and allergic rhinitis. We report here on a potent and selective, small molecule VLA-4 inhibitor, (2S)-3-(2', 5'-dichlorobiphenyl-4-yl)-2-({[1-(2-methoxybenzoyl)piperidin-3-yl]carbonyl}amino) propanoic acid, compound 1, and characterize the antagonist activities of this molecule in various cell-based assays and in an animal model of eosinophil migration. Compound 1 inhibited VLA-4/ vascular cell adhesion molecule-1(VCAM-1) interactions with in vitro potencies (IC50 value of 210 nM) in VLA-4-expressing Ramos cells, although the compound did not inhibit cell adhesion to fibronectin via alpha5beta1 integrin (very late antigen-5, VLA-5). Blockade of phorbol-12-myristate-13-acetate (PMA)- or Mn2+-stimulated VLA-4 interactions with compound 1 was observed in human T lymphocytes (IC50 value of 230 nM), human eosinophils (IC50 value of 4.0 microM) and mouse eosinophils (IC50 value of 1.6 microM). Furthermore, compound 1 administered by intraperitoneal injection inhibited eosinophil infiltration in a dose-dependent manner by up to 80% in an air pouch model. These data support the use of small molecule VLA-4 antagonists in the treatment of relevant diseases, such as asthma, atopic dermatitis, or allergic rhinitis.
MeSH terms
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Animals
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Anti-Allergic Agents / pharmacokinetics
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Anti-Allergic Agents / pharmacology*
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Anti-Allergic Agents / therapeutic use
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Anti-Inflammatory Agents / pharmacokinetics
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Anti-Inflammatory Agents / pharmacology*
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Anti-Inflammatory Agents / therapeutic use
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B-Lymphocytes / drug effects
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B-Lymphocytes / metabolism
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Cell Adhesion / drug effects
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Chemokine CCL11
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Chemokines, CC
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Chemotaxis, Leukocyte / drug effects*
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Eosinophilia / chemically induced
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Eosinophilia / metabolism
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Eosinophilia / physiopathology
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Eosinophilia / prevention & control*
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Eosinophils / drug effects*
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Eosinophils / metabolism
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Female
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Fibronectins / metabolism
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Humans
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Integrin alpha4beta1 / antagonists & inhibitors*
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Integrin alpha4beta1 / metabolism
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Integrin alpha5beta1 / metabolism
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Interleukin-5 / biosynthesis
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Interleukin-5 / genetics
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Jurkat Cells
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Lymphocyte Activation
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Transgenic
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Polychlorinated Biphenyls / pharmacokinetics
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Polychlorinated Biphenyls / pharmacology*
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Polychlorinated Biphenyls / therapeutic use
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Skin Diseases / chemically induced
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Skin Diseases / metabolism
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Skin Diseases / physiopathology
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Skin Diseases / prevention & control*
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T-Lymphocytes / drug effects
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T-Lymphocytes / metabolism
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Tetradecanoylphorbol Acetate
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Time Factors
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Vascular Cell Adhesion Molecule-1 / metabolism
Substances
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(2S)-3-(2',5'-dichlorobiphenyl-4-yl)-2-(((1-(2-methoxybenzoyl)piperidin-3-yl)carbonyl)amino)propanoic acid
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Anti-Allergic Agents
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Anti-Inflammatory Agents
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CCL11 protein, human
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Ccl11 protein, mouse
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Chemokine CCL11
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Chemokines, CC
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Fibronectins
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Integrin alpha4beta1
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Integrin alpha5beta1
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Interleukin-5
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Vascular Cell Adhesion Molecule-1
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Polychlorinated Biphenyls
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Tetradecanoylphorbol Acetate