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1、Lead Optimization - From Leads to Developmental Candidates -,1,专业调研,Why do drugs fail in clinical development?,(Taken from Kennedy, Drug Discovery Today, 2 (10), 1997, 436-444),2,专业调研,Water Solubility as a parameter for lead optimization,Is there a relationship between bioavailability and water solu
2、bility?,Yes, there is. Its called MAD! maximum absorbable dose,3,专业调研,The concept of the maximum absorbable dose (MAD): MAD = S x Ka x SIWV x SITT Swater solubility at pH 6.5 (mg/ml) Katransintestinal absorption rate constant (1/min) SIWVsmall intestinal water volume ( 250 ml) SITTsmall intestinal t
3、ransit time ( 270 min),Water Solubility as a parameter for lead optimization,Ranges 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,4,专业调研,Wate
4、r Solubility as a parameter for lead optimization,The concept of the maximum absorbable dose (MAD):,5,专业调研,How soluble does a drug candidate have to be?,Water Solubility as a parameter for lead optimization,S = MAD / (Ka x SIWV x SITT),6,专业调研,Azithromycin,Water Solubility as a parameter for lead opt
5、imization,Very poor absorption (Ka = 0.001 min-1) Very high water solubility (S = 50 mg/ml) MAD = 3375 mg Good oral bioavailability!,7,专业调研,Goals and Concepts in Lead Optimization,Increasing in-vitro potency/efficacy by bioisosteric replacement of functional groups gradual modification of 3D shape a
6、nd/or physicochemical properties Improving PC/ADME/Tox behaviour by replacement of toxophores modification of physicochemical properties (e.g. lipophilicity, charge, flexibility etc.) replacement of metabolically labile groups pro-drug concept,8,专业调研,Lead Optimization,What can be modified?,9,专业调研,Mo
7、difications of aromatic substituents,Lead Optimization,10,专业调研,Lead Optimization, Modifications of amide group,11,专业调研,Lead Optimization, Modifications of cyclohexyl group,12,专业调研,Lead Optimization, Modifications of carboxyl group,13,专业调研,Lead Optimization, Modifications of chain length,14,专业调研,Lead
8、 Optimization, Modifications of aromatic substituents,15,专业调研,The Topliss Tree A systematic lead optimization approach,16,专业调研,Lead Optimization - Example I,hormone of the thyroidal gland agonist of thyroxine receptor,bioisosterical replacements of iodo groups potent agonist of thyroxine receptor,17
9、,专业调研,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 effect,18,专业调研,analgesic drug activity due to COX inhibition,no analgesic
10、effect bioisosteric replacement of ester by amide failed!,Lead Optimization - Example III,19,专业调研,Acetyl salicylic acid: Mechanism of Action,acetyl group is transferred to serine in active site of COX = labile ester group is required!,20,专业调研,Lead Optimization - Example IVFrom Peptides to Peptidomim
11、etics,21,专业调研,Lead Optimization - Example IVFrom Peptides to Peptidomimetics,22,专业调研,The Prodrug concept,Prodrugs are weak or inactive precursers of drugs Active drug is only generated after biotransformation of prodrug by metabolic transformation by spontaneous chemical degradation Goal: improved A
12、DME/Tox- or physicochemical properties,23,专业调研,The Prodrug concept - Example I,Drug:,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 brain,24,专业调研,
13、The Prodrug concept - Example II,Drug:,Prodrug:,anti-hypertensive drug orally inactive,orally active due to amino acid carrier degradation to Enalaprilat by esterases,25,专业调研,The Prodrug concept - Example III,Drug:,Prodrug:,Morbus Parkinson drug orally inactive slow penetration of blood-brain barrie
14、r,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 decarboxylation,26,专业调研,Drug:,Prodrug:,anti-convulsive neurotransmitter orally inactive no penetratio
15、n of blood-brain barrier,orally active rapid penetration of blood-brain barrier,The Prodrug concept - Example IV,27,专业调研,Drug Discovery: Whats next?,28,专业调研,Differences between leads and drugs,(Taken from Oprea et al., J. Chem. Inf. Comput. Sci. 2001, 41, 1308-1315),Drugs compared to leads are heavi
16、er are more lipophilic have more ring systems, rotatable bonds, H-acceptors,29,专业调研,Technology,The Graffinity Approach,Small molecules are immobilized on gold surface Protein-Ligand Affinity is measured via Surface-Plasmon Resonance,30,专业调研,100 200 300 400 500 600 Molweight,1,000,000 100,000 10,000
17、1,000 100 10,Library Size,drug like,lead like,The Graffinity Approach:Screening Scenarios,31,专业调研,Diversity in Microtiterplates,Technology,LC/MS Quality control,Daughter Microarrays,The Graffinity Approach: Library Synthesis,32,专业调研,Technology,The Graffinity Approach: Library Synthesis,33,专业调研,Techn
18、ology,Minimal Amounts of Protein Protein-Ligand Affinity Maps Surface-Plasmon Resonance No Assay Development Function-Blind,The Graffinity Approach: Detection,34,专业调研,Principle of Surface Plasmon Resonance - a means to detect Protein-Ligand binding,35,专业调研,Technology,Immediate Rank-Order of Affinities,The Graffinity Approach: Detection,36,专业调研,Technology,The Graffinity Approach: SAR Analysis,37,专业调研,我使用的“设置透明色”处理的,38,专业调研,39,专业调研,