Isoquinoline derivatives as potent CRTH2 antagonists: Design, synthesis and SAR

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• 作者：Rie Nishikawa-Shimono ; Yoshinori Sekiguchi ; Takeshi Koami ; Madoka Kawamura ; Daisuke Wakasugi ; Kazuhito Watanabe ; Shunichi Wakahara ; Kayo Kimura ; Susumu Yamanobe ; Tetsuo Takayama
• 关键词：CRTH2 antagonist ; Allergic diseases ; Isoquinoline ; PGD2
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：15 December, 2013
• 年：2013
• 卷：21
• 期：24
• 页码：7674-7685
• 全文大小：1014 K

文摘

In this study, we describe the synthesis and structure-activity relationship (SAR) of a series of isoquinoline chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonists. TASP0376377 (15-20), one of the most potent compounds, showed a potent binding affinity (IC₅₀ = 19 nM) in addition to the excellent functional antagonist activity (IC₅₀ = 13 nM). Moreover, the efficacy of this compound in a chemotaxis assay (IC₅₀ = 23 nM) was in good agreement with its potency as a CRTH2 antagonist. In addition, 15-20 exhibited greater selectivity in binding to CRTH2 than to the DP1 prostanoid receptor (IC₅₀ >1 渭M) or the enzymes COX-1 and COX-2 (IC₅₀ >10 渭M).