6xfv
CRYSTAL STRUCTURE OF RAR-RELATED ORPHAN RECEPTOR C IN COMPLEX WITH A NOVEL INVERSE AGONIST
Structural highlights
FunctionRORG_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 PubMedA novel series of cis-3,4-diphenylpyrrolidines were designed as RORgammat 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 RORgammat (EC50 of 61 nM in an inverse agonist assay), selective relative to RORalpha, RORbeta, LXRalpha and LXRbeta, and stable in human and mouse liver microsomes. Furthermore, compound 31 exhibited considerably lower PXR Ymax (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/RORgammat. 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 RORgammat inverse agonists.,Jiang B, Duan JJ, Stachura S, Karmakar A, Hemagiri H, Raut DK, Gupta AK, Weigelt CA, Khan J, Sack JS, Wu DR, Yarde M, Shen DR, Galella MA, Mathur A, Zhao Q, Salter-Cid LM, Carter PH, Dhar TGM Bioorg Med Chem Lett. 2020 Sep 1;30(17):127392. doi: 10.1016/j.bmcl.2020.127392. , Epub 2020 Jul 10. PMID:32738966[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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