6o98

From Proteopedia

Crystal structure of RAR-related orphan receptor C in complex with a phenyl (3-phenylpyrrolidin-3-yl)sulfone inhibitor

Structural highlights

6o98 is a 2 chain structure with sequence from Homo sapiens. This structure supersedes the now removed PDB entry 6nxh. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.29Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RORG_HUMAN Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock.

Publication Abstract from PubMed

A new phenyl (3-phenylpyrrolidin-3-yl)sulfone series of RORgammat inverse agonists was discovered utilizing the binding conformation of previously reported bicyclic sulfonamide 1. Through a combination of structure-based design and structure-activity relationship studies, a polar set of amides at N1-position of the pyrrolidine ring and perfluoroisopropyl group at para-position of the 3-phenyl group were identified as critical structural elements to achieve high selectivity against PXR, LXRalpha, and LXRbeta. Further optimization led to the discovery of (1R,4r)-4-((R)-3-((4-fluorophenyl)sulfonyl)-3-(4-(perfluoropropan-2-yl)phenyl)pyr rolidine-1-carbonyl)cyclohexane-1-carboxylic acid (26), which displayed excellent selectivity, desirable liability and pharmacokinetic properties in vitro, and a good pharmacokinetic profile in mouse. Oral administration of 26 demonstrated dose-dependent inhibition of IL-17 production in a mouse IL-2/IL-23-induced pharmacodynamic model and biologic-like efficacy in an IL-23-induced mouse acanthosis model.

Structure-based Discovery of Phenyl (3-Phenylpyrrolidin-3-yl)sulfones as Selective, Orally Active RORgammat Inverse Agonists.,Duan JJ, Lu Z, Jiang B, Stachura S, Weigelt CA, Sack JS, Khan J, Ruzanov M, Galella MA, Wu DR, Yarde M, Shen DR, Shuster DJ, Borowski V, Xie JH, Zhang L, Vanteru S, Gupta AK, Mathur A, Zhao Q, Foster W, Salter-Cid LM, Carter PH, Dhar TGM ACS Med Chem Lett. 2019 Feb 26;10(3):367-373. doi:, 10.1021/acsmedchemlett.9b00010. eCollection 2019 Mar 14. PMID:30891142^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Duan JJ, Lu Z, Jiang B, Stachura S, Weigelt CA, Sack JS, Khan J, Ruzanov M, Galella MA, Wu DR, Yarde M, Shen DR, Shuster DJ, Borowski V, Xie JH, Zhang L, Vanteru S, Gupta AK, Mathur A, Zhao Q, Foster W, Salter-Cid LM, Carter PH, Dhar TGM. Structure-based Discovery of Phenyl (3-Phenylpyrrolidin-3-yl)sulfones as Selective, Orally Active RORgammat Inverse Agonists. ACS Med Chem Lett. 2019 Feb 26;10(3):367-373. doi:, 10.1021/acsmedchemlett.9b00010. eCollection 2019 Mar 14. PMID:30891142 doi:http://dx.doi.org/10.1021/acsmedchemlett.9b00010