Article ; Online: 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.
Journal of medicinal chemistry
2018 Volume 61, Issue 23, Page(s) 10415–10439
Abstract: 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- ...
| Abstract | 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)-1 H-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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| MeSH term(s) | Administration, Oral ; Animals ; Biological Availability ; Drug Design ; Drug Evaluation, Preclinical ; Drug Inverse Agonism ; Humans ; Mice ; Nuclear Receptor Subfamily 1, Group F, Member 3/agonists ; Pyridines/administration & dosage ; Pyridines/pharmacokinetics ; Pyridines/pharmacology ; Th17 Cells/drug effects ; Th17 Cells/metabolism | ||||||||||
| Chemical Substances | Nuclear Receptor Subfamily 1, Group F, Member 3 ; Pyridines | ||||||||||
| Language | English | ||||||||||
| Publishing date | 2018-09-09 | ||||||||||
| Publishing country | United States | ||||||||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | ||||||||||
| ZDB-ID | 218133-2 | ||||||||||
| ISSN | 1520-4804 ; 0022-2623 | ||||||||||
| ISSN (online) | 1520-4804 | ||||||||||
| ISSN | 0022-2623 | ||||||||||
| DOI | 10.1021/acs.jmedchem.8b00392 | ||||||||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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