5LWP

Discovery of phenoxyindazoles and phenylthioindazoles as RORg inverse agonists

Summary for 5LWP

• Entry DOI: 10.2210/pdb5lwp/pdb
• Descriptor: Nuclear receptor ROR-gamma, 4-[3-[2-chloranyl-6-(trifluoromethyl)phenoxy]-5-(dimethylcarbamoyl)indazol-1-yl]benzoic acid (3 entities in total)
• Functional Keywords: ror gamma allosteric ligand inverse agonistm, transcription
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P51449
• Total number of polymer chains: 1
• Total formula weight: 28993.94

Authors

Ouvry, G.,Bouix-Peter, C.,Ciesielski, F.,Chantalat, L.,Christin, O.,Comino, C.,Duvert, D.,Feret, C.,Harris, C.S.,Luzy, A.-P.,Musicki, B.,Orfila, D.,Pascau, J.,Parnet, V.,Perrin, A.,Pierre, R.,Raffin, C.,Rival, Y.,Taquet, N.,Thoreau, E.,Hennequin, L.F. (deposition date: 2016-09-19, release date: 2016-11-16, Last modification date: 2024-11-20)

Primary citation

Ouvry, G.,Bouix-Peter, C.,Ciesielski, F.,Chantalat, L.,Christin, O.,Comino, C.,Duvert, D.,Feret, C.,Harris, C.S.,Lamy, L.,Luzy, A.P.,Musicki, B.,Orfila, D.,Pascau, J.,Parnet, V.,Perrin, A.,Pierre, R.,Polge, G.,Raffin, C.,Rival, Y.,Taquet, N.,Thoreau, E.,Hennequin, L.F.
Discovery of phenoxyindazoles and phenylthioindazoles as ROR gamma inverse agonists.
Bioorg.Med.Chem.Lett., 26:5802-5808, 2016

PubMed Abstract: Targeting the IL17 pathway and more specifically the nuclear receptor RORγ is thought to be beneficial in multiple skin disorders. The Letter describes the discovery of phenoxyindazoles and thiophenoxy indazoles as potent RORγ inverse agonists. Optimization of the potency and efforts to mitigate the phototoxic liability of the series are presented. Finally, crystallization of the lead compound revealed that the series bound to an allosteric site of the nuclear receptor. Such compounds could be useful as tool compounds for understanding the impact of topical treatment on skin disease models.

PubMed: 27815118
DOI: 10.1016/j.bmcl.2016.10.023

Experimental method

X-RAY DIFFRACTION (2.4 Å)