Chiral Separation And Pharmacological Profile Of Doxazosin Enantiomers

Chirality is an important characteristic of biosystem. The basic substance such as receptors and enzymes in organisms mediating the biological and physiological responses may all be chiral. After chiral drugs enter the organisms, the enantiomers are recognized differently , and show different profiles in pharmacodynamics, pharmacokinetics and toxicology. Therefore, in the beginning of drug development, research on chirality for chiral drug should be started. The chiral research can help to design screen model for new drug with higher potency, higher selectivity, and less side effect. Furthermore, the research on the chiral drugs has significance of evaluating the racemate drug in clinical application. In this study, we chose the cti-adrenoceptor antagonist doxazosin as subject for study. Two new methods for chiral analysis and chiral separation were established using high performance capillary electrophoresis and high performance liquid chromatography with chiral mobile phase. By the methods, the two enantiomers of doxazosin were separated and prepared. The pharmacological profile and pharmakinetic characteristic of the enantiomers were elucidated. The results of the study gave some hits for the development of chiral drugs in the treatment of BPH.Part I Chiral separation of three new antagonists of alphal-adrenoceptors by high performance capillary electrophoresisChiral separation is chellenge to the research of chiral drugs, and a popular subject in analytical field. In order to establish a new method for the chiral analysis of ctradrenoceptor antagonists and use them in pharmacodynamic and pharmacokinetic studies, we applied the newtechnology, i.e. high performance capillary electrophoresis to the chiral separation. By optimizing factors such as the kind and concentration of chiral addictive, the pH and concentration of buffer, temperature and voltage, we chose the optimum conditions for the chiral separation. The enantiomers of doxazosin, terazosin and alfuzosin were base-line-separated by the new method.1. Effect of the kind and concentration of chiral addictive (cyclodextrins) on separation Among 7 kinds of cyclodextrins, CM-p-cyclodextrin was the best one which had strong ability for chiral separation. The minimum concentrations for the chiral separation of doxazosin, teazosin and alfuzosin were 7,10,6 mmol L, respectively.2. Effect of pH and concentration of buffer on chiral separation Buffer pH was one of most important factors that affect chiral separation. When pH is changed slightly, the resolution and migration time were affected significantly. The best pH values for doxazosin, terazosin and alfuzosin were 2.2. The optimum buffer concentration for doxazosin, terazosin and alfuzosin was 30, 18, 10 mmol L1 respectively.3. Effect of temperature and voltage on chiral separation When temperature was reduced, both resolution and migration time were increased. If the applied voltage was increased, the strength of electric field was increased and the charged molecule would migrate fast. To achieved the best separation result in minimum time, we chose 20 and 30kV as optimum conditions for chiral separation.CM-p-cyclodextrin is the best chiral addictive for the chiral separation of doxazosin, terazosin and alfuzosin. Buffer pH is one of the most important factors for chiral separation, especially for basic chiral drug, such as doxazosin, terazosin and alfuzosin. To achieved the high resolution and stable migration time, the fluctuation of pH should be strictly control. In comparison with pH, the change of temperature and voltage will less affect the resolution.Part II Chiral separation and preparation of doxazosin enantiomersby chiral mobile phase HPLCResearch of chiral drugs is one of the new trend for drug discovery. The study on biological effects of individual enantiomers is an important step in the drug development process. There are two ways for the preparation enantiomers. One is asymmetric synthesis...