Kummer David A, Cummings Maxwell D, Abad Marta, Barbay Joseph, Castro Glenda, Wolin Ronald, Kreutter Kevin D, Maharoof Umar, Milligan Cynthia, Nishimura Rachel, Pierce Joan, Schalk-Hihi Celine, Spurlino John, Urbanski Maud, Venkatesan Hariharan, Wang Aihua, Woods Craig, Xue Xiaohua, Edwards James P, Fourie Anne M, Leonard Kristi
Discovery Immunology, Janssen Research and Development, 3210 Merryfield Row, San Diego, CA 92121, United States.
Discovery Sciences, Janssen Research and Development, Welsh and McKean Roads, Spring House, PA 19477, United States.
Bioorg Med Chem Lett. 2017 May 1;27(9):2047-2057. doi: 10.1016/j.bmcl.2017.02.044. Epub 2017 Feb 21.
A high-throughput screen of the ligand binding domain of the nuclear receptor retinoic acid-related orphan receptor gamma t (RORγt) employing a thermal shift assay yielded a quinoline tertiary alcohol hit. Optimization of the 2-, 3- and 4-positions of the quinoline core using structure-activity relationships and structure-based drug design methods led to the discovery of a series of modulators with improved RORγt inhibitory potency and inverse agonism properties.
利用热位移分析对核受体视黄酸相关孤儿受体γt（RORγt）的配体结合域进行高通量筛选，得到了一种喹啉叔醇命中化合物。运用构效关系和基于结构的药物设计方法对喹啉核心结构的2位、3位和4位进行优化，从而发现了一系列具有改善的RORγt抑制效力和反向激动特性的调节剂。
