Zwitterionic CRTh2 Antagonists

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• 作者：Tim Luker ; Roger Bonnert ; Stuart W. Paine ; Jerzy Schmidt ; Carol Sargent ; Anthony R. Cook ; Andrew Cook ; Philip Gardiner ; Steve Hill ; Carol Weyman-Jones ; Anil Patel ; Stephen Thom ; Philip Thorne
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：March 24, 2011
• 年：2011
• 卷：54
• 期：6
• 页码：1779-1788
• 全文大小：941K
• 年卷期：v.54,no.6(March 24, 2011)
• ISSN：1520-4804

文摘

A novel series of zwitterions is reported that contains potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). A high quality lead compound 2 was discovered from virtual screening based on the pharmacophore features present in a literature compound 1. Lead optimization through side chain modification and preliminary changes around the acid are disclosed. Optimization of physicochemical properties (log D, MWt, and HBA) allowed maintenance of high CRTh2 potency while achieving low rates of metabolism and minimization of other potential concerns such as hERG channel activity and permeability. A step-change increase in potency was achieved through addition of a single methyl group onto the piperazine ring, which gave high quality compounds suitable for progression into in vivo studies.