6XFV

CRYSTAL STRUCTURE OF RAR-RELATED ORPHAN RECEPTOR C IN COMPLEX WITH A NOVEL INVERSE AGONIST

Summary for 6XFV

• Entry DOI: 10.2210/pdb6xfv/pdb
• Descriptor: Nuclear receptor ROR-gamma, 1-(4-{(3S,4S)-4-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-3-methyl-3-phenylpyrrolidine-1-carbonyl}piperidin-1-yl)ethan-1-one (3 entities in total)
• Functional Keywords: rorgt, nuclear hormone receptor, ligand-binding domain, inverse agonist, transcription-agonist complex, transcription/agonist
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 62535.99

Authors

Sack, J.S. (deposition date: 2020-06-16, release date: 2020-08-12, Last modification date: 2023-10-18)

Primary citation

Jiang, B.,Duan, J.J.,Stachura, S.,Karmakar, A.,Hemagiri, H.,Raut, D.K.,Gupta, A.K.,Weigelt, C.A.,Khan, J.,Sack, J.S.,Wu, D.R.,Yarde, M.,Shen, D.R.,Galella, M.A.,Mathur, A.,Zhao, Q.,Salter-Cid, L.M.,Carter, P.H.,Dhar, T.G.M.
Discovery of (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenyl)pyrrolidines as novel ROR gamma t inverse agonists.
Bioorg.Med.Chem.Lett., 30:127392-127392, 2020

PubMed Abstract: A novel series of cis-3,4-diphenylpyrrolidines were designed as RORγt inverse agonists based on the binding conformation of previously reported bicyclic sulfonamide 1. Preliminary synthesis and structure-activity relationship (SAR) study established (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenyl)pyrrolidine as the most effective scaffold. Subsequent SAR optimization led to identification of a piperidinyl carboxamide 31, which was potent against RORγt (EC of 61 nM in an inverse agonist assay), selective relative to RORα, RORβ, LXRα and LXRβ, and stable in human and mouse liver microsomes. Furthermore, compound 31 exhibited considerably lower PXR Y (46%) and emerged as a promising lead. The binding mode of the diphenylpyrrolidine series was established with an X-ray co-crystal structure of 10A/RORγt.

PubMed: 32738966
DOI: 10.1016/j.bmcl.2020.127392

Experimental method

X-RAY DIFFRACTION (2.15 Å)