Hypoglycemic,Potential Binding Modes,Acute Toxicity Effects And Preclinical Pharmacokinetics Study Of YG-18 As A Novel α-Glucosidase Inhibitor

Objective:YG-18,one of the series of bioactive compounds with a sulfonamide chalcone structure,has been shown to inhibitα-glucosidase activity in vitro.In the present study,YG-18 was selected as object of study,we aimed to explore its hypoglycemic effect and acute toxicity in mice,potential binding modes and pharmacokinetics,tissue distribution,excretion of YG-18 in SD rats.Methods:1.Hypoglycemic effects,potential binding modes,acute toxicity effects:Hypoglycemic effects:The mice were randomly divided into control groups,acarbose groups and YG-18(7.23mg·kg^-1)groups,receiving intragastric administration of sucrose and glucose respectively.The concentration of blood glucose was analyzed at 0,0.5,1,and2 h after intragastric administration.The area under the curve（AUC）was calculated as well.Potential binding modes:Molecular docking simulation is used to predict the interaction pattern between YG-18 and the active site of the co-crystallized structure ofα-glucosidase.Acute toxicity effects:The toxicity and survival of mice was observed at 4 h,48 h and 14 d after intragastric administration.At the end of the observation,mice were sacrificed and dissected for gross examination（including the organs’morphology,color,and texture）.2.Pharmacokinetics,tissue distribution,excretion study:Pharmacokinetics:A quantitative LC-MS/MS analysis method was established to determine the concentrations of YG-18 in SD rats plasma,tissues and excretion,the pharmacokinetic behavior of YG-18 in SD rats was investigated after low dose(2.55 mg·kg^-1),medium dose（7.23 mg·kg-1）,high dose(21.46 mg·kg^-1)oral administration and medium dose(7.23 mg·kg^-1)caudal vein administration;Tissue distribution:After oral medium dose(7.23 mg·kg^-1),drug distribution in 13 tissues including heart,liver,spleen,lung,kidney,stomach and many more,and the concentration change with time were determined;Excretion:After oral medium dose(7.23 mg·kg^-1),the cumulative excretion of urine and feces in each time period was determined to clarify the excretion characteristics in SD rats.Results:1.Hypoglycemic and toxic effects:YG-18(7.23 mg·kg^-1)lowered the peak value of blood glucose after sucrose loading in normal mice（p<0.05）and decreased the AUC of blood glucose from 0 to 2 h（p<0.001）.At the limit test dose of 2000 mg·kg^-1according to OECD guidelines,all mice survived and no toxicities except diarrhea were observed in 14 d.There were no significant changes in the organs’morphology,color and texture.Molecular docking analysis showed that YG-18 may form hydrogen bonds with GLN 279,ARG 315,GLU 411 amino acid residues and form van der Waals interaction with ASP 69,ASP 215,and GLU 277 amino acid residues ofα-glucosidase structure.2.Pharmacokinetics,tissue distribution,excretion:Pharmacokinetics:After oral administration of low,middle and high doses of YG-18 to SD rats,T_max of all rats was less than 0.3 h,and T_1/2 of all rats were less than 0.5 h;the linear regression equation between C_max（y）and dosage（x）was y=0.01414x-8.279（r=0.9593）,and the linear regression equation between AUC_0-∞（y）and dosage（x）was y=0.0269x-7.393（r=0.9545）;Tissue distribution:The oral absolute bioavailability of YG-18 was（62.5±19.9）%;The concentration of drugs in small intestine,large intestine and stomach was significantly higher than that in other organs after intragastric administration,and the concentration in small intestine tissue was the highest.Fat is relatively high in concentration compared to other tissues,and only minuscule amounts of drugs are detected in the brain;Excretion:After oral administration,the cumulative excretion of the drug in prototype from urine was more than that from feces,and the cumulative excretion barely increased after 12 h.Conclusions:This study indicated that YG-18 is a novelα-glucosidase inhibitor with a hypoglycemic effect and a high safety profile.YG-18 may form hydrogen bonds and van der Waals interaction withα-glucosidase.After oral administration,YG-18 exhibited linear pharmacokinetics in rats,and could be rapidly absorbed to reach the maximum plasma concentration with high bioavailability.After intragastric administration,YG-18 firstly distributed in large quantities in digestive organs,especially small intestine,and decreased sharply over time.Therefore,small intestine is highly likely to be the main absorption site of oral administration.Since the cumulative excretion of YG-18 of prototype drug was relatively few,it is speculated that YG-18 would be converted into metabolites and discharged from the body after entering the organism.