Details

Autor(en) / Beteiligte

• Narjes, Frank
• Xue, Yafeng
• von Berg, Stefan
• Malmberg, Jesper
• Llinas, Antonio
• Olsson, Roine I
• Jirholt, Johan
• Grindebacke, Hanna
• Leffler, Agnes
• Hossain, Nafizal
• Lepistö, Matti
• Thunberg, Linda
• Leek, Hanna
• Aagaard, Anna
• McPheat, Jane
• Hansson, Eva L
• Bäck, Elisabeth
• Tångefjord, Stefan
• Chen, Rongfeng
• Xiong, Yao
• Hongbin, Ge
• Hansson, Thomas G

Titel

Potent and Orally Bioavailable Inverse Agonists of RORγt Resulting from Structure-Based Design

Ist Teil von

• Journal of medicinal chemistry, 2018-09, Vol.61 (17), p.7796-7813

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2018

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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 favorable PK in rodents, with compound 32 representing a promising starting point for future investigations.