IL-5 is an essential cytokine for the maturation of eosinophil precursors to eosinophils, and it is those eosinophils that have been found to correlate with the severity of the late asthmatic reaction. Thus, design of IL-5 receptor antagonists that block pulmonary eosinophil disorders and present a new approach to treating allergic asthma. In Phase I, we used SBI technology to compute a 3-D dynamic model from the crystal structure of IL-5 and construct pharmacophore templates to screen large scale compound libraries in order to identify potential inhibitors of IL-5 action. Three compounds showing Ki greater than 10 uM in an IL-5 receptor plate assays were obtained. The goal of Phase II is to perform computationally guided synthetic optimizations of active lead compounds identified in Phase I and to discover selective and potent drug candidates active in a murine model for allergic asthma. The long term goal of this project is to develop at least one non-peptide IL-5 receptor antagonist as a potential anti-asthmatic and anti-allergic agent.
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