Synthesis Process Optimization Of BMS-626529 And Design,Synthesis And Bioactivity Evaluation Of Its "Me-Too" Drug

Acquired immunodeficiency syndrome(AIDS),mainly casued by HIV-1 infection,is a kind of infectious disease which seriously threatens human life and health.Currently,in the clinical,highly active antiretroviral therapies(HAART)are the most effective treatments to prevent the development of AIDS.However,the efficacy of HAART faces great challenges,due to severe side effects and the emergence of HIV-resistant mutants.Therefore,there is an urgent need to develop novel antiviral drugs with new structures and mechanisms by targeting the crucial underexplored process of HIV-1 replication.Acting in the early stage of HIV infection,fusion inhibitors can effectively prevent the fusion of HIV and target cells,which is considered to have a better application prospect in the prevention and treatment of AIDS.Developed by Bristol-Myers Squibb,BMS-626529 is a fusion inhibitor targeting gp120,which interfere with the combination of gp120 and CD4 receptor to prevent the enter of the virus.This compound displays high potent in the primary cell-based assay,but it also has the disadvantage of poor water solubility and short half-life.The prodrug of BMS-626529,Fostemsavir,has performed well in recent phase III clinical trials and is expected to be marketed in the near future.Therefore,focuing on the optimization of the synthesis process of BMS-626529 and improving its pharmacokinetic and druggability properties is of great significance for the treatment of AIDS patients in China.Part Ⅰ:Synthesis process optimization of BMS-626529It has been reported that there are many feasible schemes for the synthesis of BMS-626529.Through the analyses of these schemes,we finally determined a suitable industrial production route,with considering some important factors such as raw material price,reaction time and yield.In this route,the synthesis of BMS-626529 starts from the chemical reaction between 5-bromo-2-chloro-3-nitropyridine and vinylmagnesium to form the azaindole skeleton.Subsequently,Ullmann coupling reaction,nucleophilic substitution reaction,Friedel-Crafts acylation,ester hydrolysis reaction and amide condensation reactions take place in turn to obtain the final product.In addition,for the speed limiting step in the route,we investigated the effect of different reaction conditions on the yield.Experimental datas showed that the total yield of the optimized route is 2.31%,which is significantly higher than the yield of the original method(1.32%).It is roughly estimated that after the optimization of the production process,the main raw material cost for the production of 1Kg BMS-626529 is reduced from 521658 yuan to 339121 yuan.In conclusion,this study provides an important method for the industrial production of BMS-626529.Part Ⅱ:Design,synthesis and bioactivity evaluation of BMS-626529 "Me-Too"DrugBMS-626529 displayed high potent in the primary cell-based assay against a pseudotype virus expressing a JRFL envelope with EC50=0.14 nM.Unfortunately attributed to the low crystalline aqueous solubility of 0.022 mg/mL at pH=7.4,its bioavailability is very low,and the half-life was short at just 1.5 h.In order to improve the metabolic stability of the compound,we used an electronic isometric strategy to replace the easily metabolized amide bond with a sulfonamide bond and replaced the hydrogen atom at the para position of the benzene ring,which is easily metabolized.At the same time,we changed the benzene ring to a more polar substituted benzene ring or substituted heterocyclic ring with the purpose of improving the solubility.In this series,we synthesized a total of 20 compounds.Among them,I-cll displayed the best activity in the MT-4 cell-based assay against HIV-1 NL4-3 Nanoluc-sec strains with EC50=0.14 nM,which decreased significantly compared with the lead compound(EC50=0.14 nM).The results of molecular docking indicate that the direction of the aromatic ring extending into the inside of the binding pocket is inconsistent compared with the lead compound,which is considered to be the main reason for the decreased activity.Although the activity results of this series of compounds are not satisfactory,it provides a reference for the future modification of this class of compounds.In short,in this study,we optimized the synthesis process of BMS-626529,achieving the goals of increasing yield,reducing cost and shortening reaction time..Meanwhile,a series of "Me-too" molecules were designed and synthesized and evaluated the antiviral activity.Although no satisfactory activity was obtained,we found that the direction of the aromatic ring extending into the inside of the binding pocket is very important to antiviral activity,which provides inspiration for the structural optimization of this class of compounds in the future.