6476-17-1Relevant academic research and scientific papers
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,Kobayashi, Atsuko,Komai, Masato,Maemoto, Michihiro,Otsubo, Nobumasa,Otsubo, Shigeki,Sakaida, Yumi,Takada, Hidenori
, (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.
Substituted benzaldehydes in the darzens condensation with alkyl dihaloacetates
Mamedov,Berdnikov,Tsuboi,Hamamoto,Komiyama,Gorbunova,Gubaidullin,Litvinov
, p. 1455 - 1463 (2007/10/03)
The Darzens reaction of dihaloacetic acid esters with aromatic aldehydes produces either arylhaloglycidic or arylhalopyruvic esters depending on the nature of the substituent in the aromatic ring. Alkyl p- methoxyphenylchloropyruvates undergo spontaneous intermolecular cyclocondensation to form pyranone or furanone derivatives depending on the character of the alkyl fragment.
A highly enantioselective chemoenzymatic synthesis of syn-3-amino-2-hydroxy esters: Key intermediates for taxol side chain and phenylnorstatine
Rodrigues, J. Augusto R.,Milagre, Humberto M. S.,Milagre, Cintia D. F.,Moran, Paulo J. S.
, p. 3099 - 3106 (2007/10/03)
Starting from the bromination of α-ketoesters to obtain 3-bromo-2-oxoalkanoates and bioreduction with Saccharomyces cerevisiae entrapped in calcium alginate pellets with double gel layers, syn-(2R,3S)-β-bromo- α-hydroxy esters were obtained regioselectively in high yields and high ee. These chiral bromohydrins were cyclized to epoxides that were transformed into oxazolidines and finally opened by acidic hydrolysis to give syn-(2S,3S)-β-amino-α-hydroxy esters in high overall yields and high ee. The enantiomeric excesses of all the intermediates were maintained during the reaction sequence.
Synthesis of 2-oxazolone-4-carboxylates from 3-nosyloxy- and 3-bromo-2-ketoesters
Okonya, John F.,Hoffman, Robert V.,Johnson, M. Catherine
, p. 1102 - 1108 (2007/10/03)
New methods for the synthesis of 2-oxazolone-4-carboxylates from 3-nosyloxy- and 3-bromo-2-ketoesters are described. Condensation of 3-nosyloxy-2-ketoesters with methyl carbamate in refluxing toluene in the presence of p-TSA provided 2-oxazolone-4-carboxylates in good yields (41-80%). Alternatively, bromination of α-ketoesters with CuBr2 provided 3-bromo-2-ketoesters which condensed with methyl carbamate in the presence of p-TSA and AgOTfunder similar conditions to provide 2-oxazolone-4-carboxylates in comparable yields (30-79%). The 2-oxazolone-4-carboxylates bear functionality that can be elaborated to a variety of potentially useful compounds. For example, some of these heterocycles were readily N-acylated, reduced to alcohols, or saponified and coupled with amino acids.
