Discovery and optimization of new oxadiazole substituted thiazole RORγt inverse agonists through a bioisosteric amide replacement approach. Issue 12 (15th June 2020)

• Record Type: Journal Article
• Authors: Steeneck, Christoph; Gege, Christian; Kinzel, Olaf; Albers, Michael; Kleymann, Gerald; Schlüter, Thomas; Schulz, Andreas; Xue, Xiaohua; Cummings, Maxwell D.; Fourie, Anne M.; Leonard, Kristi A.; Scott, Brian; Edwards, James P.; Hoffmann, Thomas; Goldberg, Steven D.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 12(2020)
• Publication Date: 2020-06-15
• Subjects: Nuclear receptor -- RORγt -- RORc -- Bioisostere -- Oxadiazole -- Autoimmune diseases; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127174
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Starting from previously identified thiazole-2-carboxamides exemplified by compound 1/6, two new series of RORγt inverse agonists with significantly improved aqueous solubility, ADME parameters and oral PK properties were discovered. These scaffolds were identified from a bioisosteric amide replacement approach. Amongst the variety of heterocycles explored, a 1, 3, 4-oxadiazole led to compounds with the best overall profile for SAR development and in vivo exploration. In an ex vivo mouse PD model, concentration dependent efficacy was demonstrated and compounds 3/5 and 6/3 were profiled in a 5-day rat tolerability study.