药物优化医学宣教课件.ppt
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1、资料仅供参考,不当之处,请联系改正。Why do drugs fail in clinical development?(Taken from Kennedy,Drug Discovery Today,2(10),1997,436-444)资料仅供参考,不当之处,请联系改正。Water Solubility as a parameter for lead optimizationIs there a relationship between bioavailability and water solubility?Yes,there is.Its called MAD!maximum abso
2、rbable dose资料仅供参考,不当之处,请联系改正。The concept of the maximum absorbable dose(MAD):MAD=S x Ka x SIWV x SITTSwater solubility at pH 6.5(mg/ml)Katransintestinal absorption rate constant(1/min)SIWVsmall intestinal water volume(250 ml)SITTsmall intestinal transit time(270 min)Water Solubility as a parameter f
3、or lead optimizationRanges typical for drug candidates:Ka=0.001-0.05 min-1(50-fold)S=0.0001-100 mg/ml(106-fold)Typical dose for a drug is 1 mg/kg for a 70 kg patient,70 mg drug substance must be available in the blood资料仅供参考,不当之处,请联系改正。Ka(1/min)Solubility(mg/ml)MAD(mg)0.0030.0010.20.0030.012.030.0030
4、.120.30.0031.02030.030.0012.030.030.0120.30.030.12030.0312030Water Solubility as a parameter for lead optimizationThe concept of the maximum absorbable dose(MAD):资料仅供参考,不当之处,请联系改正。How soluble does a drug candidate have to be?Dose(mg/kg)Dose(mg)MAD(mg)Ka(1/min)Solubility(mg/ml)0.1770.0030.0350.0300.0
5、041.070700.0030.3460.0300.035107007000.0033.4600.0300.350Water Solubility as a parameter for lead optimizationS=MAD/(Ka x SIWV x SITT)资料仅供参考,不当之处,请联系改正。AzithromycinWater Solubility as a parameter for lead optimizationVery poor absorption(Ka=0.001 min-1)Very high water solubility(S=50 mg/ml)MAD=3375
6、mg Good oral bioavailability!Goals and Concepts in Lead OptimizationIncreasing in-vitro potency/efficacy bybioisosteric replacement of functional groupsgradual modification of 3D shape and/or physicochemical propertiesImproving PC/ADME/Tox behaviour byreplacement of toxophoresmodification of physico
7、chemical properties(e.g.lipophilicity,charge,flexibility etc.)replacement of metabolically labile groupspro-drug concept资料仅供参考,不当之处,请联系改正。NOHOHOHOOCLead OptimizationWhat can be modified?资料仅供参考,不当之处,请联系改正。NOHOHOHOOCHalNOHOHOHOOCCH3NOHOHOHOOCNH2NOHOHOBrBrHOOCModifications of aromatic substituentsLead
8、Optimization资料仅供参考,不当之处,请联系改正。NOHOHOHOOCNHOHOHOHOOCNHOHOHOHOOCNOHOHHOOCLead Optimization Modifications of amide group资料仅供参考,不当之处,请联系改正。NOHOHOHOOCNOHOHOHOOCNNOHOHOHOOCNONOHOHHOOCNOHOHOHOOCLead Optimization Modifications of cyclohexyl group资料仅供参考,不当之处,请联系改正。NOHOHOHOOCNOHOHONH2NOHOHONNNHNNOHOHOOOLead O
9、ptimization Modifications of carboxyl group资料仅供参考,不当之处,请联系改正。NOHOHOHOOCNOHOOCOHOHNOHOOCOHOHLead Optimization Modifications of chain length资料仅供参考,不当之处,请联系改正。NOHOHOHOOCNOOOHOOCNHalOHOOCNOHOOCNHNLead Optimization Modifications of aromatic substituents资料仅供参考,不当之处,请联系改正。The Topliss Tree A systematic lead
10、 optimization approach资料仅供参考,不当之处,请联系改正。ONH2OHIIICOOHThyroxinONH2OHCH3CH3COOHCH3CH33,5-dimethyl-3-isopropyl-thyronineLead Optimization-Example I hormone of the thyroidal gland agonist of thyroxine receptor bioisosterical replacements of iodo groups potent agonist of thyroxine receptor资料仅供参考,不当之处,请联系
11、改正。NH2OHOHDopamineNHOHOHOHCH3AdrenalineNH2CH3Amphetamine(Speed)NHOOCH3CH3MDMA(Ecstasy)Lead Optimization-Example II hydrophilic neurotransmitters orally inactive no penetration of blood-brain barrier lipophilic adrenaline mimics orally active good penetration of blood-brain barrier centrally stimulat
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