Study On The Crystal Form Of Steroid Hormone Drugs And Preliminary Screening Of New Anti-ED Drugs Targeting PDE5

This paper is divided into two parts,mainly focusing on the crystal status of steroid sex hormone drugs and the preliminary screening of new anti-ED drugs with PDE5 as the target molecule.The first part is the crystal study of steroid sex hormone drugs.The study of new drug crystal is an economical,rapid and efficient innovative drug research strategy,which is one of the hot spots in foreign countries.Up to 66%of the small-molecule new drugs approved for marketing by the FDA from 2010 to 2014 were related to the drug crystal.In 2015,the pharmacopoeia of the PRC adopted the crystal type research and crystal quality control guidelines as the reference standards for new drug development and drug quality control.Therefore,the study on the effect of drug crystal on pharmacodynamics includes:selecting the appropriate drug crystal through the confirmation of the dominant drug crystal;improving the physical and chemical properties of drugs through cocrystal;seeking for the effect of drug production process and storage process on drug crystal shape by studying crystal transformation.At present,steroid sex hormone drugs independently produced in China lag behind foreign products in terms of type and market share.It was found that there were few studies on the drug crystal types at home and abroad.Therefore,it is urgent to solve the scientific problems such as the effect of crystal type on the efficacy and quality control of such drugs.This paper carried out the study about polymorphism and cocrystal and crystal transformation of steroid hormone drugs:estradiol,and mifepristone,using infrared,nuclear magnetic,XRD,and the determination of single crystal technology.Through on the crystallization process of the drug in a wide variety of different crystal forms of structure,physical and chemical properties,stability testing analysis,confirmed the target drug preparation conditions and characteristics of different type polycrystalline state parameters,set up a new crystal structure of the drug discovery screening,preparation and identification analysis technology,which confirmed advantage crystal type or new type,of steroid hormone drug quality standard in our country,upgrading and new drug research and development to provide with scientific basis can be drawn lessons from research data.A.In this paper,two solvent complex crystal samples were screened and obtained,crystal type Ⅰ(hydrate)and crystal type Ⅱ(formamide solvent complex).Crystal type Ⅱwas first discovered,and crystal type Ⅰ was the dominant crystal type.As for cocrystal screening,and cocrystal Ⅰ and cocrystal Ⅱ were obtained as well as water-methanol compound.The newly obtained cocrystal samples were also stable compared with the commercially available estradiol crystal types,but the dissolution rate increased.Cocrystal Ⅱ is the dominant crystal type.A total of 5 polymorphs(M,A,B,C D)were obtained by mifepristone screening in the research group,among which 4(A,B,C D)were found for the first time.The test results showed that polymorph A was superior to polymorph B,with good stability and higher solubility than API crystal in some solutions.On the other hand,the different batches of commercial mifepristone API and tablets provided by the manufacturer have the same crystal shape,and there is no crystal transformation phenomenon in the stability.Temperature,humidity and light conditions during production and storage do not cause crystal transformation.The second part is about the preliminary screening of new anti-ed drugs with PDE5 as the target molecule.Screening of novel anti-ED drugs targeting PDE5.It is proposed to synthesize a batch of sildenafil targeted analogues by a new synthesis method,and obtain 1-2 lead compounds with significant anti-ed functions and promising drug development prospects through computer virtual screening,efficacy study,polycrystalline,pharmacokinetic and safety studies at different levels.We used a more efficient and environmentally friendly sildenafil synthesis path PDF conversion to produce master ring.Through the virtual screening method,the interaction between PDE5 and the candidate drug was simulated by using the molecular docking software on the computer,and the affinity between the two was calculated to reduce the actual number of compounds screened.Inhibition of phosphodiesterase was measured in vitro with PDE5A kit,and the synthesis was verified in vitro.In vivo efficacy of screening:establish proper ED animal models(a high-fat diet and STZ to make II diabetes ED model.The structure of several compounds was selected by computer simulation,and the score was high.In this model,precursors of two compounds with good enzyme inhibition effect were identified in vitro.The ED model was successfully established in this paper to provide reference experience for ED animal experimental model.The application of the virtual screening and the traditional biological experimental methods are combined,and they echo each other and complement each other.