药物优化医学宣教课件

1、Why do drugs fail in clinical development?(Taken from Kennedy, Drug Discovery Today, 2 (10), 1997, 436-444)Why do drugs fail in clinicalWater 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 doseWater Solubility as a parametThe 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 Solubil

3、ity 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 absWater Solubility as a

4、parameter for lead optimizationThe concept of the maximum absorbable dose (MAD):Water Solubility as a parametHow 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 candidAzithromycinWater Solubility as a p

5、arameter 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 Goals and Concepts in Lead OptimizationIncreasing in-vitro potency/efficacy bybioisosteric replacement of functional grou

6、psgradual 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

7、 OpLead OptimizationWhat can be modified?Lead OptimizationWhat can be Modifications of aromatic substituentsLead OptimizationModifications of aromatic Lead Optimization Modifications of amide groupLead Optimization ModificatiLead Optimization Modifications of cyclohexyl groupLead Optimization Modifi

8、catiLead Optimization Modifications of carboxyl groupLead Optimization ModificatiLead Optimization Modifications of chain lengthLead Optimization ModificatiLead Optimization Modifications of aromatic substituentsLead Optimization ModificatiThe Topliss Tree A systematic lead optimization approachThe

9、Topliss Tree A systematiLead Optimization - Example I hormone of the thyroidal gland agonist of thyroxine receptor bioisosterical replacements of iodo groups potent agonist of thyroxine receptorLead Optimization - Example ILead Optimization - Example II hydrophilic neurotransmitters orally inactive

10、no penetration of blood-brain barrier lipophilic adrenaline mimics orally active good penetration of blood-brain barrier centrally stimulating effectLead Optimization - Example I analgesic drug activity due to COX inhibition no analgesic effect bioisosteric replacement of ester by amide failed!Lead

11、Optimization - Example III analgesic drug no analgesic eAcetyl salicylic acid: Mechanism of Action acetyl group is transferred to serine in active site of COX = labile ester group is required!Acetyl salicylic acid: MechanLead Optimization - Example IVFrom Peptides to Peptidomimetics Fibrinogen binds

12、 to Fibrinogen receptor= Initiation of blood clotting Binding is inhibited by Arg-Gly-Asp (RGD)-tripeptidLead Optimization - Example ILead Optimization - Example IVFrom Peptides to PeptidomimeticsLead Optimization - Example IThe Prodrug conceptProdrugs are weak or inactive precursers of drugsActive

13、drug is only generated after biotransformation of prodrugby metabolic transformationby spontaneous chemical degradationGoal: improved ADME/Tox- or physicochemical propertiesThe Prodrug conceptProdrugs aThe Prodrug concept - Example IDrug:Prodrug: central analgesic orally inactive slow penetration of

14、 blood-brain barrier orally inactive rapid penetration of blood-brain barrier degradation to morphine in brain accumulation of morphine in brainThe Prodrug concept - ExampleThe Prodrug concept - Example IIDrug:Prodrug: anti-hypertensive drug orally inactive orally active due to amino acid carrier de

15、gradation to Enalaprilat by esterasesThe Prodrug concept - ExampleThe 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

16、 inhibitor prevents dopamine oxidation peripheral decarboxylase inhib. prevents L-Dopa decarboxylationThe Prodrug concept - ExampleDrug:Prodrug: anti-convulsive neurotransmitter orally inactive no penetration of blood-brain barrier orally active rapid penetration of blood-brain barrierThe Prodrug co

17、ncept - Example IVDrug:Prodrug: anti-convulsive Drug Discovery:Whats next?药物优化医学宣教课件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-acceptors

18、Differences between leads andTechnologyThe Graffinity ApproachSmall molecules are immobilized on gold surfaceProtein-Ligand Affinity is measured via Surface-Plasmon ResonanceTechnologyThe Graffinity Appr100 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 Diversity in MicrotiterplatesTechnologyLC/MS Quality controlDaughter MicroarraysThe Graffinity Approach: Library SynthesisDive