MEDI 248 |
| CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) and DP (D prostanoid) are G protein coupled receptors that share the same ligand, prostaglandin D2 (PGD2). However, these receptors are expressed in different cell types and may play complimentary roles. CRTH2 is expressed on eosinophils, basophils, and T helper 2 (Th2) lymphocytes and activation by PGD2 induces chemotaxis and eosinophil degranulation. DP is expressed on airway epithelium, smooth muscle and platelets and upon stimulation increases the level of cAMP and mediates flushing, sneezing, mucosal plasma exudation, and nasal blockage. Since PGD2 is released by mast cells in large amounts during asthmatic responses, it has been postulated that blocking CRTH2 and DP could be therapeutically valuable to asthma and other allergic diseases. In this presentation, we will disclose the optimization and evaluation in in vivo asthma models of a series of phenylacetic acid derivatives with potent activity against the CRTH2 and DP receptors that led to the selection of AMG 009 as a preclinical development compound. |
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New Approaches for the Treatment of Pulmonary Inflammatory Diseases
8:30 AM-11:50 AM, Wednesday, August 22, 2007 BCEC -- 210A, Oral
Division of Medicinal Chemistry |