Isoquinoline derivatives as potent CRTH2 antagonists: Design,synthesis and SAR |
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Authors: | Rie Nishikawa-Shimono Yoshinori Sekiguchi Takeshi Koami Madoka Kawamura Daisuke Wakasugi Kazuhito Watanabe Shunichi Wakahara Kayo Kimura Susumu Yamanobe Tetsuo Takayama |
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Institution: | 1. Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403, Yoshino-Cho, Kita-Ku, Saitama-Shi 331-9530, Japan;2. Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403, Yoshino-Cho, Kita-Ku, Saitama-Shi 331-9530, Japan |
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Abstract: | 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 μM) or the enzymes COX-1 and COX-2 (IC50 >10 μM). |
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Keywords: | CRTH2 antagonist Allergic diseases Isoquinoline PGD2 |
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