6r7a
Ligand complex of RORg LBDLigand complex of RORg LBD
Structural highlights
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 PubMedThe further optimization of a recently disclosed series of inverse agonists of the nuclear receptor RORC2 is described. Investigations into the left-hand side of compound 1, guided by X-ray crystal structures, led to the substitution of the 4-aryl-thiophenyl residue with the hexafluoro-2-phenyl-propan-2-ol moiety. This change resulted in to compound 28, which combined improved drug-like properties with good cell potency and a significantly lower dose, using an early dose to man prediction. Target engagement in vivo was demonstrated in the thymus of mice by a reduction in the number of double positive T cells after oral dosing. Discovery of Potent and Orally Bioavailable Inverse Agonists of the Retinoic Acid Receptor-Related Orphan Receptor C2.,von Berg S, Xue Y, Collins M, Llinas A, Olsson RI, Halvarsson T, Lindskog M, Malmberg J, Jirholt J, Krutrok N, Ramnegard M, Brannstrom M, Lundqvist A, Lepisto M, Aagaard A, McPheat J, Hansson EL, Chen R, Xiong Y, Hansson TG, Narjes F ACS Med Chem Lett. 2019 May 29;10(6):972-977. doi:, 10.1021/acsmedchemlett.9b00158. eCollection 2019 Jun 13. PMID:31223457[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||