Authors
Mark E Schnute, Mattias Wennerstål, Jennifer Alley, Martin Bengtsson, James R Blinn, Charles W Bolten, Timothy Braden, Tomas Bonn, Bo Carlsson, Nicole Caspers, Ming Chen, Chulho Choi, Leon P Collis, Kimberly Crouse, Mathias Farnegardh, Kimberly F Fennell, Susan Fish, Andrew C Flick, Annika Goos-Nilsson, Hjalmar Gullberg, Peter K Harris, Steven E Heasley, Martin Hegen, Alexander E Hromockyj, Xiao Hu, Bolette Husman, Tomasz Janosik, Peter Jones, Neelu Kaila, Elisabet Kallin, Bjorn Kauppi, James R Kiefer, John Knafels, Konrad Koehler, Lars Kruger, Ravi G Kurumbail, Robert E Kyne Jr, Wei Li, Joakim Lofstedt, Scott A Long, Carol A Menard, Scot Mente, Dean Messing, Marvin J Meyers, Lee Napierata, Daniel Noteberg, Philippe Nuhant, Matthew J Pelc, Michael J Prinsen, Patrik Rhonnstad, Eva Backstrom-Rydin, Johnny Sandberg, Maria Sandstrom, Falgun Shah, Maria Sjoberg, Aron Sundell, Alexandria P Taylor, Atli Thorarensen, John I Trujillo, John D Trzupek, Ray Unwalla, Felix F Vajdos, Robin A Weinberg, David C Wood, Li Xing, Edouard Zamaratski, Christoph W Zapf, Yajuan Zhao, Anna Wilhelmsson, Gabriel Berstein
Publication date
2018/8/21
Journal
Journal of Medicinal Chemistry
Volume
61
Issue
23
Pages
10415-10439
Publisher
American Chemical Society
Description
The nuclear hormone receptor retinoic acid receptor-related orphan C2 (RORC2, also known as RORγt) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of the receptor is anticipated to reduce production of IL-17, a key proinflammatory cytokine. Through a high-throughput screening approach, we identified a molecule displaying promising binding affinity for RORC2, inhibition of IL-17 production in Th17 cells, and selectivity against the related RORA and RORB receptor isoforms. Lead optimization to improve the potency and metabolic stability of this hit focused on two key design strategies, namely, iterative optimization driven by increasing lipophilic efficiency and structure-guided conformational restriction to achieve optimal ground state energetics and maximize receptor residence time. This approach successfully identified 3-cyano-N-(3-(1-isobutyrylpiperidin-4-yl …
Scholar articles
ME Schnute, M Wennerstål, J Alley, M Bengtsson… - Journal of Medicinal Chemistry, 2018