Journal of Medicinal Chemistry p. 10415 - 10439 (2018)
Update date:2022-08-15
Topics:
Schnute, Mark E.
Wennerstal, Mattias
Alley, Jennifer
Bengtsson, Martin
Blinn, James R.
Bolten, Charles W.
Braden, Timothy
Bonn, Tomas
Carlsson, Bo
Caspers, Nicole
Chen, Ming
Choi, Chulho
Collis, Leon P.
Crouse, Kimberly
F?rnegardh, Mathias
Fennell, Kimberly F.
Fish, Susan
Flick, Andrew C.
Goos-Nilsson, Annika
Gullberg, Hjalmar
Harris, Peter K.
Heasley, Steven E.
Hegen, Martin
Hromockyj, Alexander E.
Hu, Xiao
Husman, Bolette
Janosik, Tomasz
Jones, Peter
Kaila, Neelu
Kallin, Elisabet
Kauppi, Bj?rn
Kiefer, James R.
Knafels, John
Koehler, Konrad
Kruger, Lars
Kurumbail, Ravi G.
Kyne, Robert E.
Li, Wei
L?fstedt, Joakim
Long, Scott A.
Menard, Carol A.
Mente, Scot
Messing, Dean
Meyers, Marvin J.
Napierata, Lee
N?teberg, Daniel
Nuhant, Philippe
Pelc, Matthew J.
Prinsen, Michael J.
Rh?nnstad, Patrik
Backstr?m-Rydin, Eva
Sandberg, Johnny
Sandstr?m, Maria
Shah, Falgun
Sj?berg, Maria
Sundell, Aron
Taylor, Alexandria P.
Thorarensen, Atli
Trujillo, John I.
Trzupek, John D.
Unwalla, Ray
Vajdos, Felix F.
Weinberg, Robin A.
Wood, David C.
Xing, Li
Zamaratski, Edouard
Zapf, Christoph W.
Zhao, Yajuan
Wilhelmsson, Anna
Berstein, Gabriel
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)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide as a potent and selective RORC2 inverse agonist, demonstrating good metabolic stability, oral bioavailability, and the ability to reduce IL-17 levels and skin inflammation in a preclinical in vivo animal model upon oral administration.
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