Präsentation zum Thema: "- From Leads to Developmental Candidates -"— Präsentation transkript:
1- From Leads to Developmental Candidates - Lead Optimization- From Leads to Developmental Candidates -
2Why do drugs fail in clinical development? (Taken from Kennedy, Drug Discovery Today, 2 (10), 1997, )
3Water Solubility as a parameter for lead optimization Is there a relationship betweenbioavailability and water solubility?Yes, there is. It's called MAD!
4Water Solubility as a parameter for lead optimization The concept of the maximum absorbable dose (MAD):MAD = S x Ka x SIWV x SITTS water solubility at pH 6.5 (mg/ml)Ka transintestinal absorption rate constant (1/min)SIWV small intestinal water volume (~ 250 ml)SITT small intestinal transit time (~ 270 min)Typical dose for a drug is 1 mg/kg for a 70 kg patient,70 mg drug substance must beavailable in the bloodRanges typical for drug candidates:Ka = min-1 (50-fold)S = mg/ml (106-fold)
5Water Solubility as a parameter for lead optimization The concept of the maximum absorbable dose (MAD):
6Water Solubility as a parameter for lead optimization How soluble does a drug candidate have to be???S = MAD / (Ka x SIWV x SITT)
7Water Solubility as a parameter for lead optimization AzithromycinVery poor absorption (Ka = min-1)Very high water solubility (S = 50 mg/ml)MAD = 3375 mg Good oral bioavailability!
8Goals and Concepts in Lead Optimization Increasing 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 concept
12Lead Optimization Modifications of cyclohexyl group
13Lead Optimization Modifications of carboxyl group
14Lead Optimization Modifications of chain length
15Lead Optimization Modifications of aromatic substituents
16The Topliss Tree A systematic lead optimization approach
17Lead Optimization - Example I hormone of the thyroidal glandagonist of thyroxine receptorbioisosterical replacements of iodo groupspotent agonist of thyroxine receptor
18Lead Optimization - Example II hydrophilic neurotransmittersorally inactiveno penetration of blood-brain barrierlipophilic adrenaline mimicsorally activegood penetration of blood-brain barriercentrally stimulating effect
19Lead Optimization - Example III analgesic drugactivity due to COX inhibitionno analgesic effectbioisosteric replacement of ester by amide failed!
20Acetyl salicylic acid: Mechanism of Action acetyl group is transferred to serine in active site of COX=> labile ester group is required!
21Lead Optimization - Example IV From Peptides to Peptidomimetics Fibrinogen binds toFibrinogen receptor=> Initiation of blood clottingBinding is inhibited byArg-Gly-Asp (RGD)-tripeptid
22Lead Optimization - Example IV From Peptides to Peptidomimetics
23The Prodrug concept Prodrugs are weak or inactive precursers of drugs Active drug is only generated after biotransformation of prodrugby metabolic transformationby spontaneous chemical degradationGoal: improved ADME/Tox- or physicochemical properties
24The Prodrug concept - Example I central analgesicorally inactiveslow penetration of blood-brain barrierProdrug:orally inactiverapid penetration of blood-brain barrierdegradation to morphine in brainaccumulation of morphine in brain
25The Prodrug concept - Example II anti-hypertensive drugorally inactiveProdrug:orally active due to amino acid carrierdegradation to Enalaprilat by esterases
26The Prodrug concept - Example III Morbus Parkinson drugorally inactiveslow penetration of blood-brain barrierDrug:Prodrug:orally activerapid penetration of blood-brain barrier due to amino acid carrier!Auxillary drugs:central MAO inhibitorprevents dopamine oxidationperipheral decarboxylase inhib.prevents L-Dopa decarboxylation
27The Prodrug concept - Example IV anti-convulsive neurotransmitterorally inactiveno penetration of blood-brain barrierProdrug:orally activerapid penetration of blood-brain barrier
29Differences between leads and drugs (Taken from Oprea et al., J. Chem. Inf. Comput. Sci. 2001, 41, )Drugs compared to leadsare heavierare more lipophilichave more ring systems, rotatable bonds, H-acceptors
30The Graffinity Approach TechnologySmall molecules are immobilized on gold surfaceProtein-Ligand Affinity is measured via Surface-Plasmon Resonance
31The Graffinity Approach:Screening Scenarios Library Sizelead likedrug likeHTS of company pools1,000,000100,00010,0001,00010010GraffinitySAR by NMRCrystalLEADIn-Silico ScreensMolweight