Inhibition of eosinophilia in vivo by a small molecule inhibitor of very late antigen (VLA)-4.
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.
Okigami
Hiromi
H
Bayer Yakuhin, Ltd., Research Center Kyoto, Respiratory Disease Research, Japan. dah.okigami@cc.nara-wu.ac.jp
Takeshita
Keisuke
K
Tajimi
Masaomi
M
Komura
Hiroshi
H
Albers
Markus
M
Lehmann
Thomas E
TE
Rölle
Thomas
T
Bacon
Kevin B
KB
D000818:Animals; D018926:Anti-Allergic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D054413:Chemokine CCL11; D019742:Chemokines, CC; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004802:Eosinophilia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D004804:Eosinophils / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D039081:Integrin alpha5beta1 / Q000378:metabolism; D015848:Interleukin-5 / Q000096:biosynthesis / Q000235:genetics; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011078:Polychlorinated Biphenyls / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D012871:Skin Diseases / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
C519332:(2S)-3-(2',5'-dichlorobiphenyl-4-yl)-2-(((1-(2-methoxybenzoyl)piperidin-3-yl)carbonyl)amino)propanoic acid; D018926:Anti-Allergic Agents; D000893:Anti-Inflammatory Agents; C515456:CCL11 protein, human; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D005353:Fibronectins; D039041:Integrin alpha4beta1; D039081:Integrin alpha5beta1; D015848:Interleukin-5; D019010:Vascular Cell Adhesion Molecule-1; D011078:Polychlorinated Biphenyls; D013755:Tetradecanoylphorbol Acetate