Identification and structure activity relationships of quinoline tertiary alcohol modulators of RORγt. Issue 9 (1st May 2017)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 9(2017)
• Page Start: 2047
• Page End: 2057
• Publication Date: 2017-05-01
• Subjects: RORγt -- Retinoic acid-related orphan nuclear receptor gamma t -- Agonist -- Neutral antagonist -- Inverse agonist -- Th17 -- IL-17; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.02.044
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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.