Design,Synthesis And Preclinical Pharmacological Study Of Etomidate Analogues

Objective:In recent years,a variety of etomidate analogues have been developed,However,there is still no compound that can completely retain the advantages of etomidate without inhibiting adrenal cortex function.Besides,the previous research and development approach was mostly based on empirical design,and lots of randomized trials were used to screen potential drug candidates,which was low efficient.In this study,several candidate compounds with potential activity were synthesized by computer aided design and screening of etomidate analogs based on the reported structure-activity relationships of etomidate analogs and their binding modes to receptors.The purpose of this study was to evaluate and screen a series of in vitro and in vivo trials to explore whether an artificial intelligence-assisted drug design strategy could screen out a compound with a novel structure that retains the advantages of etomidate without the inhibitory effect of adrenocortical function.Materials and Methods:1.Design,synthesis and screening of etomidate analogues1.1 In this study,an active skeleton was improved and designed based on the previously reported pharmacophore model through computer-aided drug design.This strategy only made further structural modifications on the optional properties of the skeleton,so that many possible etomidate derivatives were designed.Then new molecules with potential activity were screened and synthesized through virtual screening and molecular docking techniques.1.2 Taking SD adult rats as experimental animals,the median effective dose(ED₅₀)of the new compounds and the control drugs propofol and etomidate were determined by the up-and-down method.Then the compounds with higher potency and fewer adverse reactions were initially screened out.The pharmacodynamics of the equivalent dose was evaluated to screen out the compounds superior to the control drugs.1.3 In vitro and in vivo experiments were conducted to evaluate whether the compounds initially screened affected the synthesis of adrenocortical hormones and to screen out the candidate compounds without adrenocortical function inhibition.1.4 From the point of view of preparations,this study tried to make the target compound into salt,or do further structural optimization.2.Pharmacodynamic study and safety evaluation of the target compound2.1 The target compound and the control drugs were injected into adult SD rats through the tail vein,respectively.The ED₅₀,median lethal dose(LD₅₀)and therapeutic index（TI）were determined.2.2 The pharmacodynamics of the target compound and the control drugs were evaluated at the equivalent dose in SD rats of different ages.2.3 In vitro and in vivo experiments were conducted to assess the inhibitory effects of the target compounds on adrenocortical function.2.4 The effects of the target compound on the circulatory function of the experimental animals were evaluated in normal SD rats of different ages and in unstable circulatory models3.Preliminary exploration of the metabolic characteristics of the target compound3.1 The possible metabolic pathways and metabolites of the target compound were explored in different species of hepatocytes in vitro.3.2 To verify the rationality of species selection,the metabolites of target compounds in hepatocytes of different species were compared.Results:1.1 In this study,a series of etomidate derivatives were designed and simulated by computer.According to the results of virtual screening,four new compounds with a docking score higher than etomidate were synthesized and expected to have potential activities.1.2 In adult SD rats,efficacy tests showed that all the four compounds had sedative and hypnotic effects,two of which had the same potency as etomidate,and the other two had the same potency as propofol but greater potency than etomidate.1.3 At the equivalent dose of a single tail vein injection,all the compounds showed rapid onset（within 1 minute）and rapid recovery（about 10 minutes）for most of them,as did the control drugs.In addition,the occurrence of adverse reactions of these compounds was as good as that of the control drugs,and none of these compounds affected the respiratory system,such as slowing or pausing breathing.1.4 In vitro cortical function test showed that one compound might inhibit the synthesis of corticosteroids.In vivo cortical function test,compound ET-1 was finally screened as having no adrenal cortical function inhibition.1.5 The solubility of compound ET-1 was poor after salting,and the target compound ET-11B was obtained after further structural optimization.2.1 The compound ET-11B retains the advantages of etomidate,and its potency and safety range are greater than that of propofol.In addition,it can act and recover quickly in adult rats,and the recovery time in old rats is slightly longer than that of control drugs.In addition,the types and incidence of adverse reactions of this compound were significantly lower than those of the control drugs.2.2 The dose-response relationship of compound ET-11B in the cortical function test in vitro was similar to that of CPMM.The compound ET-11B had no inhibitory effect on the synthesis of adrenocortical hormone in cortical function test in vivo.2.3 The compound ET-11B had a slight effect on circulation in different age groups and hemorrhagic shock models,which was similar to that of etomidate.3.1 Preliminary results showed that the compound ET-11B showed no specific metabolic pathway in rat and monkey hepatocytes in vitro,and the main metabolites were the same.Besides the animal species selected in this study are reasonable.Conclusion:Based on the artificial intelligence-assisted drug design strategy,a new compound that retain the advantages of etomidate without the inhibitory effect of adrenocortical function was screened out in this study.Besides the screening strategy in this study is more goal-oriented,and it is easier to screen new compounds with research and development prospects.Etomidate analogue ET-11B,as a new candidate intravenous anesthetic,is worthy of further development and research.