Novel Selective Orally Active CRTH2 Antagonists for Allergic Inflammation Developed from in Silico Derived Hits

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• 作者：Trond Ulven ; Jean-Marie Receveur ; Marie Grimstrup ; &Oslash ; ystein Rist ; Thomas M. Frimurer ; Lars-Ole Gerlach ; Jesper Mosolff Mathiesen ; Evi Kostenis ; Lena Uller ; Thomas Hö ; gberg
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：November 16, 2006
• 年：2006
• 卷：49
• 期：23
• 页码：6638 - 6641
• 全文大小：90K
• 年卷期：v.49,no.23(November 16, 2006)
• ISSN：1520-4804

文摘

Hits from an in silico derived focused library for CRTH2were transformed into highly selective antagonists with favorableADME properties. Oral administration of 4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetic acid (19) inhibited peribronchialeosinophilia and mucus cell hyperplasia in a mouse model of allergicasthma, supporting the therapeutic potential of this novel compoundclass. In addition, this selective pharmacological tool compoundprovides further evidence for CRTH2 as a relevant therapeutic targetfor treatment of Th2- and eosinophil-related inflammation.