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Novel inhibitors of cell adhesion for the treatment of asthma Allergies including asthma represent a common and complicated clinical challenge. In the US alone there are 50-60 million sufferers. Together seasonal allergies and asthma represent a major strain on healthcare resources accounting for 18.5 million physician visits, almost 2 million emergency room visits and $13 billion in direct costs per year in the US. Economic costs are considerably larger due to the number of working days lost to both conditions. Although more than 50 products are on the market for asthma and allergy, considerable preclinical research is currently underway with much current focus being placed on the infiltration of eosinophils. Reducing eosinophilia can be achieved by preventing the release of activity of chemotactic molecules of by blocking cell trafficking. Inhibitors of alpha4beta1/vascular cell adhesion molecule-1 (VCAM-1) interactions offer an excellent example of the latter. At least 15 molecules with this profile are in development, most of which are still in preclinical phases for inflammatory diseases for asthma, although a few are being evaluated for arthritis and multiple sclerosis. Pfizer researchers have recently published data describing several small molecule inhibitors of alpha4beta1/VCAM-1 interactions with nanomolar-sub-nanomolar in vitro potencies (CP-664511; CP-609643). These 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. These data support the utility of small molecule alpha4beta1 antagonists in the treatment of relevant diseases, such as asthma. Link to journal abstract:
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