Indole-N-glucoside, TA-1887 As a Sodium Glucose Cotransporter 2 Inhibitor
Abstract
Inhibition of the renal sodium glucose cotransporter (SGLT) increases urinary glucose excretion (UGE) and thus reduces blood glucose levels during hyperglycemia.
To explore the potential of new antihyperglycemic agents, we synthesized and determined the human SGLT2 (hSGLT2) inhibitory potential of novel substituted 3-benzylindole-N-glucosides 6.
Optimization of 6 resulted in the discovery of 3-(4-cyclopropylbenzyl)-4-fluoroindole-N-glucoside 6a-4 (TA-1887), a highly potent and selective hSGLT2 inhibitor, with pronounced antihyperglycemic effects in high-fat diet-fed KK (HF-KK) mice.
Our results suggest the potential of indole-N-glucosides as novel antihyperglycemic agents through inhibition of renal SGLT2.
Keywords:
The Starting Oxindole was first alufa-Arylated by the Cossy's protocol, to this 2-benzylderivative is then N-glycosylated at N1 to form N-glycosylated 2-Benzyl Derivative that can be reduced by NaBH4-ZrCl4 to form the isomeric 2-benzyl-N-glycosyl Indole; this process ca offer the isomeric indoles. And more interestingly, the Benzimidazole congeners with 2-substituted benzyl Address might be an intriguing cmpound in comparison with 2-substituted Indoles.
返信削除Alternative synthetic pathway can utilize C-3 indole acylatio via Friedel-Crafts type reaction with the corresponding Acyl chloride or Acid itself. Further option for C-3 benzyl substituent can develope via Buchwald C-alkylation with such benzyl derivatives as Bn-COOR or Bn-SO2Ar, which could be removed by the conventional decarboxylation or reductive desulfonylation.
返信削除☆N-GlucosidDerivative of Other CSiCS could offer another opportunity for Drug Discovery based on the Benzoazacycles that can be related to the amide sorougate structures made by Trp and Tyr etc. These amide surrougates are Oxigaen-related structures and definately different from CNS surougates consisting of Nitrogen contaning peptides such as Hist, Arg, Glu, and Gln.
返信削除Five Membered Ring & Six Membered Rings are accomodative for Drug Scafolds and Prevalent in all living Cells; That means simple tactics for Modern Drug Developement and more convenient Drug Renovation=the most cost effective way for hunting Drug Substances in the nearlest Bush in our Town.
返信削除