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
12、ing effect资料仅供参考,不当之处，请联系改正。OOCOOHAcetyl salicylic acidNHOCOOHAmide derivative analgesic drug activity due to COX inhibition no analgesic effect bioisosteric replacement of ester by amide failed!Lead Optimization-Example III资料仅供参考,不当之处，请联系改正。Acetyl salicylic acid:Mechanism of Action acetyl group is
13、transferred to serine in active site of COX=labile ester group is required!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)-tripeptid资料仅供参考,不当之处，请联系改正。Lead Opti
14、mization-Example IVFrom Peptides to PeptidomimeticsONHNH2NHH3NONHONHOOOArg-Gly-Asp(RGD)OONHNNNNOHNHONHOOOcyclo-(Arg-Gly-Asp-Phe-d-Val)NHNNNNOCH3NHONHOOOSOSNHNHNCOOHNH2NHOOThe Prodrug conceptProdrugs are weak or inactive precursers of drugsActive drug is only generated after biotransformation of prod
15、rugby metabolic transformationby spontaneous chemical degradationGoal:improved ADME/Tox-or physicochemical properties资料仅供参考,不当之处，请联系改正。The Prodrug concept-Example IOOHOHNCH3MorphineDrug:OOONCH3CH3OCH3ODiacetyl-morphine(Heroin)Prodrug:central analgesic orally inactive slow penetration of blood-brain
16、barrier orally inactive rapid penetration of blood-brain barrier degradation to morphine in brain accumulation of morphine in brain资料仅供参考,不当之处，请联系改正。NHNOOOCH3OOEnalapril-diesterThe Prodrug concept-Example IINHNOOHOCH3OHOEnalaprilatDrug:NHNOOOCH3OHOEnalaprilProdrug:anti-hypertensive drug orally inact
17、ive orally active due to amino acid carrier degradation to Enalaprilat by esterasesNOOCH3NOODiketopiperazin derivative资料仅供参考,不当之处，请联系改正。The Prodrug concept-Example IIINH2OHOHDopamineDrug:NH2OHOHCOOHL-DopaProdrug:Morbus Parkinson drug orally inactive slow penetration of blood-brain barrier orally act
18、ive rapid penetration of blood-brain barrier due to amino acid carrier!Auxillary drugs:NCH3CH3CHSelegilin central MAO inhibitor prevents dopamine oxidationNNHOHOHOHOHNH2OBenserazid peripheral decarboxylase inhib.prevents L-Dopa decarboxylation资料仅供参考,不当之处，请联系改正。NH2OHOGABA(gamma-amino butyric acid)Dru
19、g:NClFNH2OOHProgabidProdrug:anti-convulsive neurotransmitter orally inactive no penetration of blood-brain barrier orally active rapid penetration of blood-brain barrierThe Prodrug concept-Example IV资料仅供参考,不当之处，请联系改正。Drug Discovery:Whats next?资料仅供参考,不当之处，请联系改正。Differences between leads and drugs(Tak
20、en 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
21、 via Surface-Plasmon Resonance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 ScreensGraffinity资料仅供参考,不当之处，请联系改正。Diversity in Microtiterplate
22、sTechnology LC/MS Quality control Daughter MicroarraysThe Graffinity Approach:Library Synthesis资料仅供参考,不当之处，请联系改正。TechnologyThe Graffinity Approach:Library Synthesis资料仅供参考,不当之处，请联系改正。Technology Minimal Amounts of Protein Protein-Ligand Affinity Maps Surface-Plasmon Resonance No Assay Development Func
23、tion-BlindThe Graffinity Approach:Detection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 binding资料仅供参考,不当之处，请联系改正。TechnologyImmediate Rank-Order of AffinitiesThe Graffinity Approach:Detection资料仅供参考,不当之处，请联系改正。TechnologyThe Graffinity Approach:SAR Analysis资料仅供参考,不当之处，请联系改正。我使用的“设置透明色”处理的资料仅供参考,不当之处，请联系改正。
