6613-41-8Relevant articles and documents
Discovery and mechanistic study of thiazole-4-acylsulfonamide derivatives as potent and orally active ChemR23 inhibitors with a long-acting effect in cynomolgus monkeys
Imaizumi, Takamichi,Otsubo, Shigeki,Maemoto, Michihiro,Kobayashi, Atsuko,Komai, Masato,Takada, Hidenori,Sakaida, Yumi,Otsubo, Nobumasa
, (2022/01/24)
Plasmacytoid dendritic cells (pDCs) are a subset of dendritic cells that can secrete large amounts of type I interferon. ChemR23, a G protein-coupled receptor (GPCR) expressed on the surface of pDCs, contributes to the recruitment of pDCs to inflamed tissues through chemotaxis signaling, and is therefore considered an attractive target for the treatment of autoimmune diseases. We previously reported benzoxazole-based compounds that can inhibit ChemR23 signaling through receptor internalization. Although these compounds showed ChemR23 internalization on pDCs in cynomolgus monkeys after oral administration, further improvement of the pharmacokinetics profile was needed for a clinical candidate and we therefore attempted scaffold-hopping from the benzoxazole core structure leading to novel thiazole derivatives. In this report, the design, synthesis, and biological evaluation of new thiazole-based ChemR23 inhibitors were described. Through sequential structure–activity relationship studies regarding (i) the side chain of the N-acylsulfonamide moiety, (ii) the 5-position of the thiazole ring, and (iii) the 1,2,4-oxadiazol-5-one moiety, we have succeeded in finding a potent thiazole-based ChemR23 inhibitor, 14f (IC80 = 12 nM). In addition, the oral administration of 14f at 30 mg/kg to cynomolgus monkeys demonstrated a sustained pharmacological effect of ChemR23 internalization on pDCs until 8 h after dosing, which was considered a longer effect in comparison to previously reported 2-aminobenzoxazole-based ChemR23 inhibitors. This report also shows the synthesis and evaluation of fluorescein-labeled compound 45c for a mechanistic study, and we could confirm the direct binding of our thiazole derivative to ChemR23. We believe that our research on small molecule ChemR23 inhibitors and chemical probe will contribute to the elucidation and analysis of the functions of ChemR23 as well as identifying novel therapeutics for autoimmune diseases.
ANTIDIABETIC ENOLIC GLUCOSIDE OF PHENYLPYRUVIC ACID
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Paragraph 0082; 0083; 0084; 0095; 0096, (2018/09/22)
PROBLEM TO BE SOLVED: To provide an antidiabetic enolic glucoside of phenylpyruvic acid and derivatives thereof, for use as medicaments, especially normoglycemic agents, i.e. for lowering blood glucose levels to normal levels in mammals that are obese, pre-diabetic or have diabetes, obesity and/or syndrome X. SOLUTION: Compounds of the present invention help to manage blood glucose levels, i.e. helping the body by balancing the blood glucose levels; helping to keep balanced blood glucose levels, particularly in humans with diabetes; aiding by enhancing the glucose uptake by the cells and by reducing blood glucose levels, thus improving or restoring the glucose tolerance; optimizing the glycemic response; and normalizing the glucose tolerance. SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT
Copper/ascorbic acid dyad as a catalytic system for selective aerobic oxidation of amines
Srogl, Jiri,Voltrova, Svatava
experimental part, p. 843 - 845 (2009/07/11)
A new, environmentally benign system based on an ascorbic acid (vitamin C)/copper dyad is presented, which facilitates the oxidation of amines to carbonyl compounds. The oxidation utilizes aerobic oxygen as the ultimate electron scavenger, which accepts electrons in a cascade-like fashion via a Cu+/Cu2+ and ascorbic/dehydroascorbic acid couple. Dehydroascorbic acid, the oxidation agent, finally oxidizes amine substrates in a selective fashion after forming a Schiff base intermediate. The selectivity as well as generality of the method is demonstrated on various substrates.
