7JH2

CRYSTAL STRUCTURE OF RAR-RELATED ORPHAN RECEPTOR C IN COMPLEX WITH A POTENT, SELECTIVE AND ORALLY BIOAVAILABLE ROR-GAMMA-T INVERSE AGONIST

Summary for 7JH2

• Entry DOI: 10.2210/pdb7jh2/pdb
• Descriptor: Nuclear receptor ROR-gamma, 2-({[2-(4-{(3R)-1-(4-acetylpiperazine-1-carbonyl)-3-[(4-fluorophenyl)sulfonyl]pyrrolidin-3-yl}phenyl)-1,1,1,3,3,3-hexafluoropropan-2-yl]oxy}methyl)-3-fluorobenzonitrile, SULFATE ION, ... (4 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: 63132.39

Authors

Sack, J.S. (deposition date: 2020-07-20, release date: 2020-08-12, Last modification date: 2023-10-18)

Primary citation

Duan, J.J.,Jiang, B.,Lu, Z.,Stachura, S.,Weigelt, C.A.,Sack, J.S.,Khan, J.,Ruzanov, M.,Wu, D.R.,Yarde, M.,Shen, D.R.,Zhao, Q.,Salter-Cid, L.M.,Carter, P.H.,Murali Dhar, T.G.
Discovery of 2,6-difluorobenzyl ether series of phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfones as surprisingly potent, selective and orally bioavailable ROR gamma t inverse agonists.
Bioorg.Med.Chem.Lett., 30:127441-127441, 2020

PubMed Abstract: In an effort to discover oral inverse agonists of RORγt to treat inflammatory diseases, a new 2,6-difluorobenzyl ether series of cyclopentyl sulfones were found to be surprisingly more potent than the corresponding alcohol derivatives. When combined with a more optimized phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone template, the 2,6-difluorobenzyl ethers yielded a set of very potent RORγt inverse agonists (e.g., compound 26, RORγt Gal4 EC 11 nM) that are highly selective against PXR, LXRα and LXRβ. After optimizing for stability in human and mouse liver microsomes, compounds 29 and 38 were evaluated in vivo and found to have good oral bioavailability (56% and 101%, respectively) in mice. X-ray co-crystal structure of compound 27 in RORγt revealed that the bulky benzyl ether group causes helix 11 of the protein to partially uncoil to create a new, enlarged binding site, which nicely accommodates the benzyl ether moiety, leading to net potency gain.

PubMed: 32736080
DOI: 10.1016/j.bmcl.2020.127441

Experimental method

X-RAY DIFFRACTION (2.367 Å)