Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403, Yoshino-Cho, Kita-Ku, Saitama-Shi 331-9530, Japan.
Bioorg Med Chem. 2013 Dec 15;21(24):7674-85. doi: 10.1016/j.bmc.2013.10.025. Epub 2013 Oct 30.
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).
在这项研究中，我们描述了一系列异喹啉趋化因子受体同源分子表达在 Th2 细胞上的（CRTH2）拮抗剂的合成和构效关系（SAR）。TASP0376377（15-20）是最有效的化合物之一，除了具有优异的功能性拮抗剂活性（IC50=13 nM）外，还显示出很强的结合亲和力（IC50=19 nM）。此外，该化合物在趋化作用测定中的效力（IC50=23 nM）与其作为 CRTH2 拮抗剂的效力一致。此外，15-20 在与 CRTH2 结合方面的选择性大于与 DP1 前列腺素受体（IC50 >1 μM）或酶 COX-1 和 COX-2（IC50 >10 μM）的结合。
