1. Potent and Orally Bioavailable Inverse Agonists of RORγt Resulting from Structure-Based Design
- Author
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Hanna Grindebacke, Frank Narjes, Eva L. Hansson, Yao Xiong, Antonio Llinas, Linda Thunberg, Jesper Malmberg, Stefan Tångefjord, Roine I. Olsson, Ge Hongbin, Rongfeng Chen, Yafeng Xue, Agnes Leffler, Hanna Leek, Thomas Hansson, Elisabeth Bäck, Jane McPheat, Nafizal Hossain, Matti Lepistö, Stefan von Berg, Johan Jirholt, and Anna Aagaard
- Subjects
Models, Molecular ,0301 basic medicine ,Drug Inverse Agonism ,Protein Conformation ,Stereochemistry ,Administration, Oral ,Biological Availability ,Rodentia ,Crystallography, X-Ray ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Amide ,Acetamides ,Drug Discovery ,Animals ,Humans ,Inverse agonist ,Structure–activity relationship ,Tissue Distribution ,Binding site ,Cells, Cultured ,Orphan receptor ,Binding Sites ,Molecular Structure ,Interleukin-17 ,Nuclear Receptor Subfamily 1, Group F, Member 3 ,Retinoic acid receptor ,030104 developmental biology ,chemistry ,Drug Design ,Th17 Cells ,Molecular Medicine ,Acetamide ,Protein Binding - Abstract
Retinoic acid receptor related orphan receptor γt (RORγt), 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 cocrystal structures. Efforts in targeting the cofactor-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 DMSO molecule binding in a subpocket 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 favorab...
- Published
- 2018