6CN5

HUMAN RETENOID-RELATED ORPHAN RECEPTOR-GAMMA LIGAND- BINDING DOMAIN IN COMPLEX WITH INDOLE LIGAND CP9b IN INVERSE AGONIST CONFORMATION

Summary for 6CN5

• Entry DOI: 10.2210/pdb6cn5/pdb
• Descriptor: Nuclear receptor ROR-gamma, 4-cyano-N-{3-[1-(cyclohexanecarbonyl)piperidin-4-yl]-1-methyl-1H-indol-5-yl}pyridine-2-carboxamide (3 entities in total)
• Functional Keywords: ror gamma, ligand-binding, nuclear receptor, non steroidal, indole, pfizer, inverse agonist, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 61440.96

Authors

Kauppi, B.,Vajdos, F. (deposition date: 2018-03-07, release date: 2018-09-05, Last modification date: 2023-10-04)

Primary citation

Schnute, M.E.,Wennerstal, M.,Alley, J.,Bengtsson, M.,Blinn, J.R.,Bolten, C.W.,Braden, T.,Bonn, T.,Carlsson, B.,Caspers, N.,Chen, M.,Choi, C.,Collis, L.P.,Crouse, K.,Farnegardh, M.,Fennell, K.F.,Fish, S.,Flick, A.C.,Goos-Nilsson, A.,Gullberg, H.,Harris, P.K.,Heasley, S.E.,Hegen, M.,Hromockyj, A.E.,Hu, X.,Husman, B.,Janosik, T.,Jones, P.,Kaila, N.,Kallin, E.,Kauppi, B.,Kiefer, J.R.,Knafels, J.,Koehler, K.,Kruger, L.,Kurumbail, R.G.,Kyne Jr., R.E.,Li, W.,Lofstedt, J.,Long, S.A.,Menard, C.A.,Mente, S.,Messing, D.,Meyers, M.J.,Napierata, L.,Noteberg, D.,Nuhant, P.,Pelc, M.J.,Prinsen, M.J.,Rhonnstad, P.,Backstrom-Rydin, E.,Sandberg, J.,Sandstrom, M.,Shah, F.,Sjoberg, M.,Sundell, A.,Taylor, A.P.,Thorarensen, A.,Trujillo, J.I.,Trzupek, J.D.,Unwalla, R.,Vajdos, F.F.,Weinberg, R.A.,Wood, D.C.,Xing, L.,Zamaratski, E.,Zapf, C.W.,Zhao, Y.,Wilhelmsson, A.,Berstein, G.
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.
J. Med. Chem., 61:10415-10439, 2018

PubMed 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.

PubMed: 30130103
DOI: 10.1021/acs.jmedchem.8b00392

Experimental method

X-RAY DIFFRACTION (2.3 Å)