Discovery of a New Class of Potent, Selective, and Orally Bioavailable CRTH2 (DP2) Receptor Antagonists for the Treatment of Allergic Inflammatory Diseases

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• 作者：Stefano Crosignani ; Patrick Page ; Marc Missotten ; V&#xe9 ; ronique Colovray ; Christophe Cleva ; Jean-Fran&#xe7 ; ois Arrighi ; John Atherall ; Jackie Macritchie ; Thierry Martin ; Yves Humbert ; Maril&#xe8 ; ne G
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：April 10, 2008
• 年：2008
• 卷：51
• 期：7
• 页码：2227 - 2243
• 全文大小：717K
• 年卷期：v.51,no.7(April 10, 2008)
• ISSN：1520-4804

文摘

A novel chemical class of potent chemoattractant receptor-homologous expressed on Th2 lymphocytes (CRTH2 or DP2) antagonists is reported. An initial and moderately potent spiro-indolinone compound (5) was found during a high-throughput screening campaign. Structure−activity relationship (SAR) investigation around the carboxylic acid group revealed that changes in this part of the molecule could lead to a reversal of functional activity, yielding weakly potent agonists. SAR investigation of the succinimide functional group led to the discovery of several single-digit nanomolar antagonists. The potency of these compounds was confirmed in a human eosinophil chemotaxis assay. Moreover, compounds (R)-58 and (R)-71 were shown to possess pharmacokinetic properties suitable for development as an orally bioavailable drug.