1287747-65-2Relevant academic research and scientific papers
Discovery of 3-Cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonist
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
, p. 10415 - 10439 (2018)
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.
RORC2 INHIBITORS AND METHODS OF USE THEREOF
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, (2016/03/22)
The present invention provides compounds, pharmaceutical compositions, methods of inhibiting RORγ activity and/or reducing the amount of IL-17 in a subject, and methods of treating various medical disorders using such compounds and pharmaceutical compositions.
N-(IMIDAZOLIDIN-2-YLIDENE)-HETEROCYCLOPENTA[b]PYRIDINE DERIVATIVES AS MODULATORS OF ALPHA 2 ADRENERGIC RECEPTORS
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, (2013/03/26)
The present invention relates to novel N-(imidazolidin-2-ylidene)-heterocyclo penta[b]pyridine derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals.
2H-PYRROL-5-AMINE DERIVATIVES AS ALPHA ADRENERGIC RECEPTOR MODULATORS
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Page/Page column 34, (2011/04/26)
Compounds are described herein useful for treating diseases and conditions by modulation of one or more alpha adrenergic receptor. The compounds can include a naphthalene, a quinoline, a benzoimidazole or an isoquinoline as a core structure. Methods of ma
