Topic 7.2 INTRODUCTION TO DRUG DESIGN

1 Topic TO DRUGDESIGNC hapter 11 PatrickContentsContentsPart 1: Sections drug and membrane alkyl Masking or removing polar polar Electronic shielding of / replace susceptible metabolic susceptible metabolic susceptible metabolic chemically susceptible a biosynthetic building drugs to monoclonal gut peripheral regions over drug toxicityDrug DESIGN and developmentDrug DESIGN and development Stages:Stages: 1) Identify target disease 2) Identify drug target 3) Establish testing procedures 4) Find a lead compound 5) Structure Activity Relationships (SAR) 6) Identify a pharmacophore 7) Drug DESIGN - optimising target interactions 8) Drug DESIGN - optimising pharmacokinetic properties 9) Toxicological and safety tests10) Chemical development and production11) Patenting and regulatory affairs12) Clinical trials1. Pharmacokinetics 1. Pharmacokinetics drug DESIGN drug designAimsAims To improve pharmacokinetic properties of lead compound To optimise chemical and metabolic stability (stomach acids / digestive enzymes / metabolic enzymes) To optimise hydrophilic / hydrophobic balance (solubility in blood / solubility in GIT / solubility through cell membranes / access to CNS / excretion rate) Drugs must be polar - to be soluble in aqueous conditions - to interact with molecular targets Drugs must be fatty - to cross cell membranes - to avoid rapid excretion Drugs must have both hydrophilic and lipophilic characteristics Many drugs are weak bases with pKa s 6-8 Receptor interaction& water solubilityCrossesmembranes+ HHNNHH- H1.

2 Pharmacokinetics 1. Pharmacokinetics drug DESIGN drug Vary alkyl Vary alkyl substituentsRationale: Varying the size of alkyl groups varies the hydrophilic /hydrophobic balance of the structure Larger alkyl groups increase hydrophobicityDisadvantage: May interfere with target binding for steric reasonsMethods: Often feasible to remove alkyl groups from heteroatoms andreplace with different alkyl groups Usually difficult to remove alkyl groups from the carbon skeleton -full synthesis often Solubility and membrane Solubility and membrane Vary alkyl Vary alkyl substituentssubstituentsMethylene Methylene Shuffle!Shuffle!OCH3 SOONNCH3 NHNNNCH3CH3 OViagraExtra Solubility and membrane Solubility and membrane MaskingMasking or removing polar groups or removing polar groupsRationale: Masking or removing polar groups decreases polarity and increaseshydrophobic characterDisadvantages: Polar group may be involved in target binding Unnecessary polar groups are likely to have been removed already(simplification strategy) See also prodrugsMethods:ROHROMeCH3 IRNHRCH3 COClRHNOCH3 RCOHOH+ / R'OHRCOR' Solubility and membrane Solubility and membrane Adding polar Adding polar groupsRationale:Rationale: Adding polar groups increases polarity and decreases hydrophobiccharacter Useful for targeting drugs vs.

3 Gut infections Useful for reducing CNS side effectsDisadvantage:Disadvantage: May introduce unwanted side effectsAntifungal agent with poor solubility - skin infections onlyClClCOHNNSClTioconazoleSystemic antifungal agent improved blood Solubility and membrane Solubility and membrane Vary Vary pKpKaaRationale: Varying pKa alters percentage of drug which is ionized Alter pKa to obtain required ratio of ionised to unionised drugDisadvantage: May affect binding interactionsMethod: Vary alkyl substituents on amine nitrogens Vary aryl substituents to influence aromatic amines or aromaticcarboxylic Solubility and membrane Solubility and membrane permeabilityAntithromboticbut too basicDecreased basicityN locked into Vary Vary pKpKaaH2 NNHNHONONN(I) Solubility and membrane Solubility and membrane permeabilityTerminal Steric Steric ShieldsRationale: Used to increase chemical and metabolic stability Introduce bulky group as a shield Protects a susceptible functional group ( ester) from hydrolysis Hinders attack by nucleophiles or enzymesBlocks hydrolysis of terminal Drug Drug stabilityAntirheumatic Electronic shieldingElectronic shielding of NH of NH22 Rationale: Used to stabilise labile functional groups ( esters) Replace labile ester with more stable urethane or amide Nitrogen feeds electrons into carbonyl group and makes it lessreactive Increases chemical and metabolic Drug Drug Electronic shieldingElectronic shielding of NH of NH22 RNHCR'ORNHCR' Drug Drug stabilitySee Stereoelectronic Stereoelectronic EffectsEffectsRationale: Steric and electronic effects used in combination Increases chemical and metabolic stabilityortho Methyl groups act as steric shields &hinder hydrolysis by esterasesAmide more stable than ester(electronic effect)See also.

4 Oxacillin and See also: oxacillin and bethanecholbethanecholLocal anaesthetic(short duration) Drug Drug stabilityRationale: Replace susceptible group with a different group without affectingactivity Bio-isostere shows improved pharmacokinetic properties Bio-isosteres are not necessarily isosteresPyrrole ring = bioisostere for amide Examples: Amides and urethanes for esters (see earlier) Du122290 (dopamine antagonist) Drug Drug stabilityRationale: Metabolism of drugs usually occur at specific sites. Introducegroups at a susceptible site to block the reaction Increases metabolic stability and drug lifetimeOral contraceptive - limited Metabolic Metabolic Drug Drug stabilityRationale: Metabolism of drugs usually occurs at specific groups. Remove susceptible group or replace it with metabolically stablegroup [ modification of tolbutamide (antibiotic)]Susceptible groupUnsusceptible Remove / replace susceptible metabolic Remove / replace susceptible metabolic groupsMetabolismTOLBUTAMIDEMeSOONHCONHCH 2CH2CH2CH3 NHCH2CH2CH3 CONHSOOClRapidly excreted - short Drug Drug stabilityRationale:Rationale: Used if the metabolically susceptible group is important for binding Shift its position to make it unrecognisable to metabolic enzyme Must still be recognizable to targetExample:Example:SalbutamolSalbutam olSusceptible groupUnsusceptible Shifting susceptible metabolic Shifting susceptible metabolic Drug Drug stabilitymetabolicallysusceptibleRationa le:Rationale: Used to decrease metabolic stability and drug lifetime Used for drugs which linger too long in the body and cause sideeffects Add groups known to be susceptible to Phase I or Phase II metabolicreactionsExample:Example.

5 Anti-arthritic Introducing susceptible metabolic Introducing susceptible metabolic Drug Drug stabilityRationale: Used to decrease drug lifetime Avoids reliance on metabolic enzymes and individual variationsExample:Example: Atracurium Atracurium - neuromuscular blocking agent- neuromuscular blocking agent Stable at acid pH, unstable at blood pH (slightly alkaline) Self destructs by Hoffmann elimination and has short lifetime Allows anaesthetist to control dose levels accurately Quick recovery times after Introducing chemically susceptible Introducing chemically susceptible groupsNCH2CH2 COOMeOOMeHN(CH2) Drug Drug stabilityRationale: Drug smuggled into cell by carrier proteins for natural building block( amino acids or nucleic acid bases) Increases selectivity of drugs to target cells and reduces toxicity toother cellsExample: Anticancer drugs Alkylating group is attached to a nucleic acid base Cancer cells grow faster than normal cells and have a greaterdemand for nucleic acid bases Drug is concentrated in cancer cells - Trojan horse Linking a biosynthetic building Linking a biosynthetic building Drug Drug targetingNon selective alkylating agentToxicNClClH3 CUracil MustardHNHNOONClClExample:Example:Antica ncer agentsRationale:Rationale: Identify an antigen which is overexpressed on a cancer cell Clone a monoclonal antibody for the antigen Attach a drug or poison ( ricin) to the monoclonal antibody Antibody carries the drug to the cancer cell Drug is released at the cancer Linking drugs to monoclonal Linking drugs to monoclonal Drug Drug targetingRationale:Rationale.

6 DESIGN the antibacterial agent to be highly polar or ionizedDesign the antibacterial agent to be highly polar or ionized Agent will be too polar to cross the gut wallAgent will be too polar to cross the gut wall Agent will be concentrated at the site of infectionAgent will be concentrated at the site of infection Example - highly ionized Example - highly ionized Targeting gut Targeting gut Drug Drug targetingRationale:Rationale: Increase polarity of the drug Drug is less likely to cross the blood brain Targeting peripheral regions over Targeting peripheral regions over Drug Drug targetingRationale:Rationale: Toxicity is often due to specific functional groups Remove or replace functional groups known to be toxic aromatic nitro groups aromatic amines bromoarenes hydrazines polyhalogenated groups hydroxylamines Vary substituents Vary position of Reducing drug Reducing drug toxicityExample - varying Example - varying substituentssubstituents Fluconazole Fluconazole ((DiflucanDiflucan) - antifungal agent) - antifungal agentClClCOHNNNNNNUK-47265 Substituents variedLess Reducing drug Reducing drug toxicityContentsContentsPart 2: Sections Prodrugs to improve membrane N-Methylation of Horse Prodrugs to prolong Mask polar Add hydrophobic groupsDefinition:Definition:Inactive compounds which are converted to active compounds inthe.

7 Improving membrane permeability Prolonging activity Masking toxicity and side effects Varying water solubility Drug targeting Improving chemical Prodrugs Prodrugs to improve membrane permeabilityto improve membrane Esters Used to mask polar and ionisable carboxylic acids Hydrolysed in blood by esterases Used when a carboxylic acid is required for target binding Leaving group (alcohol) should ideally be non toxicExample:Example:EnalaprilEnalapril for for enalaprilateenalaprilate (antihypertensive) (antihypertensive)ONHOROCO2 HNCH3R=Et EnalaprilR=H Prodrugs Prodrugs to improve membrane permeabilityto improve membrane permeabilityExample:Example:CandoxatrilC andoxatril for for CandoxatrilatCandoxatrilat (protease inhibitor) (protease inhibitor) Varying the ester varies the rate of hydrolysis Electron withdrawing groups increase rate of hydrolysis( 5-indanyl) Leaving group (5-indanol) is non toxicCandoxatrilatHNOOCO2 HOMeHOOHNOOCO2 HOMeOOCandoxatril5-indanyl Prodrugs Prodrugs to improve membrane permeabilityto improve membrane NN-Methylation -Methylation of aminesof amines Used to reduce polarity of amines Demethylated in liverExample:Example.

8 HexobarbitoneHexobarbitoneNNHMeOOOMeDopa mine Useful in treating Parkinson sDisease Too polar to cross cell membranesand BBBL evodopa More polar but is an amino acid Carried across cell membranesby carrier proteins for aminoacids Decarboxylated in cell Prodrugs to improve membrane Prodrugs to improve membrane Trojan Horse Trojan Horse Strategy Prodrug designed to mimic biosynthetic building block Transported across cell membranes by carrier proteinsExample: Example: Levodopa for Prodrugs Prodrugs to improve membrane permeabilityto improve membrane permeabilityCOOHH2NL-DopaCOOHH2 NEnzymeDopamineH2 NBloodsupplyBraincellsBLOOD BRAIN BARRIERE xample:Example: Azathioprine Azathioprine for 6-mercaptopurinefor 6-mercaptopurine6-Mercaptopurine(suppres ses immune response) Short lifetime - eliminated too quicklyAzathioprine Slow conversion to 6-mercaptopurine Longer Prodrugs Prodrugs to prolong activityto prolong Mask polar Mask polar groups Reduces rate of excretionNHSHNNNNNNNSNNO2 NMeHExample:Example: Valium Valium for for Prodrugs to prolong Prodrugs to prolong activityValiumNordazepamN-DemethylationN NOMeClClNHONE xample:Example:Cycloguanil pamoate Cycloguanil pamoate ((antimalarialantimalarial)) Add hydrophobic Add hydrophobic groups Drug (and counterion) concentrated in fat tissue Slow removal of hydrophobic group Slow release into blood Prodrugs Prodrugs to prolong activityto prolong activityLipophilicLipophilicPamoateCyclo guanilNNNClMeMeNH3H3 NCH2CO2 OHOHCO2 Example:Example.

9 Hydrophobic esters of Hydrophobic esters of fluphenazine fluphenazine (antipsychotic)(antipsychotic) Prodrugs to prolong Prodrugs to prolong Add hydrophobic Add hydrophobic groups Given by intramuscular injection Concentrated in fatty tissue Slowly released into the blood supply Rapidly hydrolysed in the blood supplySHNCF3 NNO(CH2)8CH3 Ofatty ester