Pulmonary eosinophilia in a murine model of allergic inflammation is attenuated by small molecule alpha4beta1 antagonists.
Inhibition of alpha4beta1/vascular cell adhesion molecule-1 (VCAM-1) interactions have therapeutic potential in treating allergic airway disease because of the importance of these adhesion molecules in the trafficking of eosinophils, lymphocytes, and monocytes. We examined several small molecule inhibitors of alpha4beta1/VCAM-1 interactions with in vitro potencies (IC(50) values) ranging from 0.52 nM (CP-664511; 3-[3-(1-[2-[3-methoxy-4-(3-O-tolyl-ureido)phenyl]-acetylamino]-3-methyl-butyl)isoxazol-5-yl]-propionic acid) to 38.5 nM (CP-609643; 3-[3-methyl-1-[2-[4-(3-O-tolyl-ureido)-phenyl]-acetylamino]-butyl)-isoxazol-5-yl]-propionic acid). The same compounds were evaluated in vivo using a murine model of ovalbumin-induced pulmonary eosinophilia. In this model, systemic administration of antibodies against alpha4 reduced bronchoalveolar lavage (BAL) eosinophilia approximately 60%. Small molecule alpha4beta1 antagonists were administered by intratracheal instillation and demonstrated dose-dependent inhibition of BAL eosinophil numbers and achieved a maximum inhibition of approximately 60%. In general, the rank order of potency for these compounds in vitro was consistent with that observed in vivo, which confirms that their efficacy is likely via blockade of alpha4beta1/VCAM-1 interactions. The most potent compound, CP-664511, also inhibited BAL eosinophilia following s.c. administration (1-10 mg/kg, s.c.). These data support the utility of small molecule alpha4beta1 antagonists in the treatment of relevant diseases, such as asthma.
Kudlacz
E
E
Pfizer Global Research and Development, Groton, Connecticut 06340, USA. elizabeth_m_kudlacz@groton.pfizer.com
Whitney
C
C
Andresen
C
C
Duplantier
A
A
Beckius
G
G
Chupak
L
L
Klein
A
A
Kraus
K
K
Milici
A
A
D000818:Animals; D018926:Anti-Allergic Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006801:Humans; D006967:Hypersensitivity / Q000209:etiology; D007249:Inflammation / Q000209:etiology; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007555:Isoxazoles / Q000627:therapeutic use*; D019169:Jurkat Cells; D051379:Mice; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D011657:Pulmonary Eosinophilia / Q000150:complications / Q000188:drug therapy*; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
D018926:Anti-Allergic Agents; C454104:CP 664511; D039041:Integrin alpha4beta1; D016023:Integrins; D007555:Isoxazoles; D010671:Phenylurea Compounds; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1