1235841-38-9Relevant academic research and scientific papers
Potent and Orally Bioavailable Inverse Agonists of RORγt Resulting from Structure-Based Design
Narjes, Frank,Xue, Yafeng,Von Berg, Stefan,Malmberg, Jesper,Llinas, Antonio,Olsson, Roine I.,Jirholt, Johan,Grindebacke, Hanna,Leffler, Agnes,Hossain, Nafizal,Lepist?, Matti,Thunberg, Linda,Leek, Hanna,Aagaard, Anna,McPheat, Jane,Hansson, Eva L.,B?ck, Elisabeth,Tangefjord, Stefan,Chen, Rongfeng,Xiong, Yao,Hongbin, Ge,Hansson, Thomas G.
, p. 7796 - 7813 (2018)
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.
SYNERGISTIC FUNGICIDAL COMPOSITIONS INCLUDING HYDRAZONE DERIVATIVES AND COPPER
-
Page/Page column 20, (2010/08/08)
The present invention relates to the use of mixtures containing hydrazone compounds and copper for controlling the growth of fungi.
