Synthetic Route of C4H7NO2SIn 2020 ,《Optimization and biological evaluation of thiazole-bis-amide inverse agonists of RORγt》 was published in Bioorganic & Medicinal Chemistry Letters. The article was written by Gege, Christian; Albers, Michael; Kinzel, Olaf; Kleymann, Gerald; Schlueter, Thomas; Steeneck, Christoph; Hoffmann, Thomas; Xue, Xiaohua; Cummings, Maxwell D.; Spurlino, John; Milligan, Cynthia; Fourie, Anne M.; Edwards, James P.; Leonard, Kristi; Coe, Kevin; Scott, Brian; Pippel, Dan; Goldberg, Steven D.. The article contains the following contents:
The nuclear receptor retinoic acid receptor-related orphan receptor gamma t (RORγt) is a transcription factor that drives Th17 cell differentiation and IL-17 production in both innate and adaptive immune cells. The IL-23/IL-17 pathway is implicated in major autoimmune and inflammatory diseases. RORγt lies at the core of this pathway and represents an attractive opportunity for intervention with small mol. therapeutics. Despite diverse chem. series having been reported, combining high potency and nuclear receptor selectivity with good physicochem. properties remains a challenging endeavor in the field of RORγt drug discovery. We recently described the discovery and evaluation of a new class of potent and selective RORγt inverse agonists based on a thiazole scaffold. Herein we describe the successful optimization of this class by incorporation of an addnl. amide moiety at the 4-position of the thiazole core. In several optimization cycles, we have reduced human PXR activation, improved solubility, and increased potency while maintaining nuclear receptor selectivity. X-ray crystallog. anal. of compound 1g bound in the sterol binding site of the ligand binding domain of RORγt was largely consistent with an earlier structure, guiding further insight into the mol. mechanism for RORγt inhibition with this series. Compound 1g is orally bioavailable, potent in a human whole blood assay and proved to be efficacious in an ex-vivo IL-17A assay, and was selected for preclin. evaluation.Ethyl 2-amino-2-thioxoacetate(cas: 16982-21-1Synthetic Route of C4H7NO2S) was used in this study.
Ethyl 2-amino-2-thioxoacetate(cas: 16982-21-1) belongs to anime. To avoid the problem of multiple alkylation, methods have been devised for “blocking” substitution so that only one alkyl group is introduced. The Gabriel synthesis is one such method; it utilizes phthalimide, C6H4(CO)2NH, whose one acidic hydrogen atom has been removed upon the addition of a base such as KOH to form a salt.Synthetic Route of C4H7NO2S
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