Improved Synthesis Of The Key Intermediate Compound Of YT-14 And Synthesis And Activity Evaluation Of GLP-1R Allosteric Modulators

YT-14 is a broad-spectrum,high-efficiency candidate drug for multi-drug resistant Gram-negative bacteria developed by our group.It shows strong activity to multidrug-resistant Escherichia coli,Klebsiella,Acinetobacter and aeruginosa in vitro and vivo.4,5-bis(benzhydryloxy)-2-(1-((1,3-dioxoisoindolin-2-yl)oxy)-2-methylpropyl)pyridine 1-oxide is the key intermediate of YT-14 and the synthsis of it is relatively complicated.In this article,we optimized the synthesis route of intermediate 10 and removed the redundant protective group.In this way,we simplified the reaction from 9 steps to 7 steps and increased the yield from 3 % To 10 %.What's more,it almost gets rid of column chromatography operation.And with this route,we completed the hundred grams synthetic scale in the laboratory.This work is of great significance for the subsequent development of YT-14.The GLP-1 receptor agonists exert the good neuroprotective effect in both the central and peripheral nervous systems,showing its potential value in the treatment of neurological diseases such as Alzheimer's disease and Parkinson's disease.In this paper,we traced the newly reported indole-pyridone molecule 39,which is a GLP-1 allosteric regulator having anti-Parkinson function,then designed and synthesed 14 new indole-pyridone compounds and evaluated the agonistic and allosteric effects on GLP-1 receptors in vitro.The results indicate that some compounds have certain allosteric regulation effects on GLP-1(7-36)a or GLP-1(9-36)a.