药物优化医学宣教课件

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)Why do drugs fail in clinical1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 absorbable doseWater Solubility as a paramet2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 for 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 bloodThe concept of the maximum abs3资料仅供参考,不当之处，请联系改正。Water Solubility as a parameter for lead optimizationThe concept of the maximum absorbable dose(MAD):Water Solubility as a paramet4资料仅供参考,不当之处，请联系改正。How soluble does a drug candidate have to be?Water Solubility as a parameter for lead optimizationS=MAD/(Ka x SIWV x SITT)How soluble does a drug candid5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 mg Good oral bioavailability!AzithromycinWater Solubility 6Goals 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 physicochemical properties(e.g.lipophilicity,charge,flexibility etc.)replacement of metabolically labile groupspro-drug conceptGoals and Concepts in Lead Op7资料仅供参考,不当之处，请联系改正。Lead OptimizationWhat can be modified?Lead OptimizationWhat can be 8资料仅供参考,不当之处，请联系改正。Modifications of aromatic substituentsLead OptimizationModifications of aromatic 9资料仅供参考,不当之处，请联系改正。Lead Optimization Modifications of amide groupLead Optimization Modificati10资料仅供参考,不当之处，请联系改正。Lead Optimization Modifications of cyclohexyl groupLead Optimization Modificati11资料仅供参考,不当之处，请联系改正。Lead Optimization Modifications of carboxyl groupLead Optimization Modificati12资料仅供参考,不当之处，请联系改正。Lead Optimization Modifications of chain lengthLead Optimization Modificati13资料仅供参考,不当之处，请联系改正。Lead Optimization Modifications of aromatic substituentsLead Optimization Modificati14资料仅供参考,不当之处，请联系改正。The Topliss Tree A systematic lead optimization approachThe Topliss Tree A systemati15资料仅供参考,不当之处，请联系改正。Lead Optimization-Example I hormone of the thyroidal gland agonist of thyroxine receptor bioisosterical replacements of iodo groups potent agonist of thyroxine receptorLead Optimization-Example I16资料仅供参考,不当之处，请联系改正。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 stimulating effectLead Optimization-Example I17资料仅供参考,不当之处，请联系改正。analgesic drug activity due to COX inhibition no analgesic effect bioisosteric replacement of ester by amide failed!Lead Optimization-Example III analgesic drug no analgesic e18资料仅供参考,不当之处，请联系改正。Acetyl salicylic acid:Mechanism of Action acetyl group is transferred to serine in active site of COX=labile ester group is required!Acetyl salicylic acid:Mechan19资料仅供参考,不当之处，请联系改正。Lead Optimization-Example IVFrom Peptides to Peptidomimetics Fibrinogen binds to Fibrinogen receptor=Initiation of blood clotting Binding is inhibited by Arg-Gly-Asp(RGD)-tripeptidLead Optimization-Example I20资料仅供参考,不当之处，请联系改正。Lead Optimization-Example IVFrom Peptides to PeptidomimeticsLead Optimization-Example I21The Prodrug conceptProdrugs are weak or inactive precursers of drugsActive drug is only generated after biotransformation of prodrugby metabolic transformationby spontaneous chemical degradationGoal:improved ADME/Tox-or physicochemical propertiesThe Prodrug conceptProdrugs a22资料仅供参考,不当之处，请联系改正。The Prodrug concept-Example IDrug:Prodrug:central analgesic orally inactive slow penetration of blood-brain barrier orally inactive rapid penetration of blood-brain barrier degradation to morphine in brain accumulation of morphine in brainThe Prodrug concept-Example23资料仅供参考,不当之处，请联系改正。The Prodrug concept-Example IIDrug:Prodrug:anti-hypertensive drug orally inactive orally active due to amino acid carrier degradation to Enalaprilat by esterasesThe Prodrug concept-Example24资料仅供参考,不当之处，请联系改正。The Prodrug concept-Example IIIDrug:Prodrug:Morbus Parkinson drug orally inactive slow penetration of blood-brain barrier orally active rapid penetration of blood-brain barrier due to amino acid carrier!Auxillary drugs:central MAO inhibitor prevents dopamine oxidation peripheral decarboxylase inhib.prevents L-Dopa decarboxylationThe Prodrug concept-Example25资料仅供参考,不当之处，请联系改正。Drug:Prodrug:anti-convulsive neurotransmitter orally inactive no penetration of blood-brain barrier orally active rapid penetration of blood-brain barrierThe Prodrug concept-Example IVDrug:Prodrug:anti-convulsive 26资料仅供参考,不当之处，请联系改正。Drug Discovery:Whats next?药物优化医学宣教课件27资料仅供参考,不当之处，请联系改正。Differences between leads and drugs(Taken from Oprea et al.,J.Chem.Inf.Comput.Sci.2001,41,1308-1315)Drugs compared to leads are heavier are more lipophilic have more ring systems,rotatable bonds,H-acceptorsDifferences between leads and28资料仅供参考,不当之处，请联系改正。TechnologyThe Graffinity ApproachSmall molecules are immobilized on gold surfaceProtein-Ligand Affinity is measured via Surface-Plasmon ResonanceTechnologyThe Graffinity Appr29资料仅供参考,不当之处，请联系改正。100 200 300 400 500 600 Molweight1,000,000100,00010,0001,00010010HTS of company poolsLibrary Sizedrug likelead likeThe Graffinity Approach:Screening ScenariosSAR by NMRCrystalLEADIn-Silico ScreensGraffinity100 200 30资料仅供参考,不当之处，请联系改正。Diversity in MicrotiterplatesTechnologyLC/MS Quality controlDaughter MicroarraysThe Graffinity Approach:Library SynthesisDiversity in MicrotiterplatesT31资料仅供参考,不当之处，请联系改正。TechnologyThe Graffinity Approach:Library SynthesisTechnologyThe Graffinity Appr32资料仅供参考,不当之处，请联系改正。TechnologyMinimal Amounts of ProteinProtein-Ligand Affinity MapsSurface-Plasmon ResonanceNo Assay DevelopmentFunction-BlindThe Graffinity Approach:DetectionTechnologyMinimal Amounts of P33资料仅供参考,不当之处，请联系改正。Principle of Surface Plasmon Resonance-a means to detect Protein-Ligand bindingPrinciple of Surface Plasmon 34资料仅供参考,不当之处，请联系改正。TechnologyImmediate Rank-Order of AffinitiesThe Graffinity Approach:DetectionTechnologyImmediate Rank-Order35资料仅供参考,不当之处，请联系改正。TechnologyThe Graffinity Approach:SAR AnalysisTechnologyThe Graffinity Appr36资料仅供参考,不当之处，请联系改正。我使用的“设置透明色”处理的我使用的“设置透明色”处理的37资料仅供参考,不当之处，请联系改正。药物优化医学宣教课件38