Design,Synthesis And Activity Studies Of PTP-1B Inhibitors Based On Imidazolidine-2,4-dione Scaffold

Objective:With the human standard of living elevating,the incidence of diabetes grows rapidly.Diabetes has been the third largest disease threated to human life after the cardiovascular disease and cancer.As the primary negative regulator in the insulin signaling pathway,protein tyrosine phosphatase-1B(PTP-1B)dephosphorylates phosphotyrosine residues of the active insulin receptor and insulin receptor substrates,and disrupts the insulin signal transduction.Recent PTP1B gene knock-out studies and anti-sense oligonucleotide(ASO)treatment in mice have identified PTP1B as a potential target for chemotherapy of diabetes and obesity.Research of PTP-1B inhibitors has been the focus on insulin sensitizer study,thus the research of PTP-1B and PTP-1B inhibitors appears to be a very attractive area for the therapy of type 2 diabetes.To identify potent PTP-1B inhibitors,with advanced device of computer-aided design,we selected imidazolidine-2,4-dione as scaffold;we introduced substitutes at C5 and N1 positions of imidazolidine-2,4-dione for acquiring lead compounds with better anti-diabetic activity and lower toxicity.Method:1.Starting from para-methoxylphenylamine,para-methoxylbenzylamine and para-methoxylphenethyl-amine as the materials,we gain imidazolidine-2,4-dione scaffold,which is substituted at the N1 position.2.5-(3-hydroxybenzylidene)imidazolidine-2,4-dione is obtained by the reaction of 3-hydroxybenzaldehyde and imidazolidine-2,4-dione.And then reacted with benzyl chloride,1-chloro-benzyl chloride,4-chloro-benzyl chloride,4-methoxy-benzyl chloride,ethyl-2-bromoacetate,2,4-dichloro-benzyl chloride,3,4-dichloro-benzyl chloride,(2-chloroethyl)benzene,(3-chloropropyl)benzene,2-chloro-1-phenylethanone,3-(chloromethyl)pyridine hydrochloride,which can provide the substituents to its-OH.3.Activity test:animal experiment is put into practice among 1-(4-methoxyphenyl)imidazolidine-2,4-dione(IZD-C0C1),1-(4-methoxybenzyl)imidazolidine-2,4-dione(IZD-H2O),1-(4-methoxyphenethyl)imidazolidine-2,4-dione(IZD-C2),5-(3-hydroxy benzylidene)imidazolidine-2,4-dione(m-IZD)and Pioglitazone,which can provide the active data to us.The experimental animal is healthy ICR mice,male and female half and half.Results:1.4-methoxyphenyl,4-methoxybenzyl and 4-methoxyphenethyl are successfully introduced into the N1 position of imidazolidine-2,4-Dione.And their structures have been characterized by 1H-NMR and MS.2.5-(3-hydroxy benzylidene)imidazolidine-2,4-Dione(m-IZD)is obtained,with the yield of 62.8%and high purity.The structures of it and its derivatives have also been characterized by 1H-NMR and MS.3.The result of the activity test show that IZD-C0C1 and IZD-H2O possess anti-diabetic activity,and can provide agonism to the target,their inhibition rate is 12%and 33%.IZD-C2 and m-IZD both get the minus inhibition rate,which are-40%and-9%,so they can provide antagonism to the target.Conclusions:The method of the synthetic route is simple,the conditions are mild,the materials are easily,available,and with good reproducibility.Therefore,the reaction time is the key factor to dertermine the yields of each substituted products.IZD-C0C1 and IZD-H2O possess anti-diabetic activity,so the structural modification of these two compounds may provide new compounds with higher activity.