7TM Pharma A/S, Fremtidsvej 3, DK-2970 Hørsholm, Denmark.
Bioorg Med Chem Lett. 2010 Feb 1;20(3):1177-80. doi: 10.1016/j.bmcl.2009.12.008. Epub 2009 Dec 4.
Structure-activity relationships of three related series of 4-phenylthiazol-5-ylacetic acids, derived from two hits emanating from a focused library obtained by in silico screening, have been explored as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) antagonists. Several compounds with double digit nanomolar binding affinity and full antagonistic efficacy for human CRTH2 receptor were obtained in all subclasses. The most potent compound was [2-(4-chloro-benzyl)-4-(4-phenoxy-phenyl)-thiazol-5-yl]acetic acid having an binding affinity of 3.7nM and functional antagonistic effect of 66 nM in a BRET and 12 nM in a cAMP assay with no functional activity for the other PGD2 DP receptor (27 microM in cAMP).
我们研究了源自计算机筛选获得的靶向文库的两个命中物衍生的三个相关系列的 4-苯基噻唑-5-基乙酸，以探讨其作为 CRTH2（嗜曙红细胞趋化因子同源物表达在 Th2 细胞上）拮抗剂的构效关系。在所有子类中，均获得了具有双位数纳摩尔结合亲和力和对人 CRTH2 受体的完全拮抗功效的几种化合物。最有效的化合物是[2-（4-氯苄基）-4-（4-苯氧基苯基）-噻唑-5-基]乙酸，在 BRET 中具有 3.7nM 的结合亲和力，在 cAMP 测定中具有 66nM 的功能拮抗作用，对其他 PGD2 DP 受体（cAMP 中 27 microM）没有功能活性。
