6esn | pdb_00006esn
Ligand 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 PubMedRetinoic acid receptor-related orphan receptor gammat (RORgammat), has been identified as the master regulator of TH17 cell function and development, making it an attractive target for the treatment of autoimmune diseases by a small molecule approach. Herein we describe our investigations on a series of 4-aryl-thienyl acetamides, which were guided by insights from X-ray co-crystal structures. Efforts in targeting the co-factor recruitment site from the 4-aryl group on the thiophene led to a series of potent binders, with nanomolar activity in a primary human TH17 cell assay. The observation of a molecule of DMSO binding in a sub-pocket outside the LBD inspired the introduction of an acetamide into the benzylic position of these compounds. Hereby, a hydrogen bond interaction of the introduced acetamide oxygen with the backbone amide of Glu379 was established. This greatly enhanced the cellular activity of previously weakly cell active compounds. The best compounds combined potent inhibition of IL-17 release with favorable PK in rodents with compound 32 representing a promising starting point for future investigations. Structure-based design leads to potent and orally bioavailable inverse agonists of RORgammat.,Narjes F, Xue Y, von Berg S, Malmberg J, Llinas A, Olsson RI, Jirholt J, Grindebacke H, Leffler A, Hossain N, Lepisto M, Thunberg L, Leek H, Aagaard A, McPheat J, Hansson EL, Back E, Tangefjord S, Chen R, Xiong Y, Hongbin G, Hansson T J Med Chem. 2018 Aug 10. doi: 10.1021/acs.jmedchem.8b00783. PMID:30095900[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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