Presentation is loading. Please wait.

Presentation is loading. Please wait.

1 MEDICINAL CHEMISTRY I (PharmD) 2012 Topic 3: Drug Design and Discovery Dr. Tareq Abu-Izneid & Dr. Munjed Ibrahim

Similar presentations


Presentation on theme: "1 MEDICINAL CHEMISTRY I (PharmD) 2012 Topic 3: Drug Design and Discovery Dr. Tareq Abu-Izneid & Dr. Munjed Ibrahim"— Presentation transcript:

1 1 MEDICINAL CHEMISTRY I (PharmD) 2012 Topic 3: Drug Design and Discovery Dr. Tareq Abu-Izneid & Dr. Munjed Ibrahim drmunjed97@yahoo.com

2 2 Resources Text  Patrick, G.L., 4 th edn., Part C (Chapters, 12, 13 and 14)  Lemke, T.L., & Williams, D.A., 6th edn, Ch 1

3 Objectives  Outline, describe & give examples of the 12 stages of drug discovery & development process  Drug Targets (Enzymes and receptors)  Sources of Lead Compounds (Sources of drugs)  Isolation and purification  Structure determination  Impact of the human genome project  SAR and Pharmacophore  Optimisations of lead compound  Optimising bonding interactions  optimising pharmacokinetic properties  Prodrugs  Aims  Examples 3

4 The Drug Discovery & Development Process 4

5 Stages: 1) Identify target disease 2) Identify drug target 2) Identify drug target 3) Establish testing procedures 3) Establish testing procedures 4) Find a lead compound 4) Find a lead compound 5) Structure Activity Relationships (SAR) 5) Structure Activity Relationships (SAR) 6) Identify a pharmacophore 6) Identify a pharmacophore 7) Drug design- optimising target interactions 7) Drug design- optimising target interactions 8) Drug design - optimising pharmacokinetic properties 8) Drug design - optimising pharmacokinetic properties 9) Toxicological and safety tests 9) Toxicological and safety tests 10) Chemical development and production 11) Patenting and regulatory affairs 12) Clinical trials The Drug Discovery & Development Process 5

6 1. Target Disease (Choosing a disease!)  Priority for the Pharmaceutical Industry Can the profits from marketing a new drug outweigh the cost of developing and testing that drug?Can the profits from marketing a new drug outweigh the cost of developing and testing that drug?  Questions to be addressed Is the disease widespread?Is the disease widespread? (e.g. cardiovascular disease, ulcers, malaria) Does the disease affect the first world?Does the disease affect the first world? (e.g. cardiovascular disease, ulcers) Are there drugs already on the market?Are there drugs already on the market? If so, what are there advantages and disadvantages?If so, what are there advantages and disadvantages? (e.g. side effects) Can one identify a market advantage for a new therapy?Can one identify a market advantage for a new therapy? Choosing which disease to tackle is a matter for a company’s market strategists!! 6

7 Stages: 1) Identify target disease 1) Identify target disease 2) Identify drug target 2) Identify drug target 3) Establish testing procedures 3) Establish testing procedures 4) Find a lead compound 4) Find a lead compound 5) Structure Activity Relationships (SAR) 5) Structure Activity Relationships (SAR) 6) Identify a pharmacophore 6) Identify a pharmacophore 7) Drug design- optimising target interactions 7) Drug design- optimising target interactions 8) Drug design - optimising pharmacokinetic properties 8) Drug design - optimising pharmacokinetic properties 9) Toxicological and safety tests 9) Toxicological and safety tests 10) Chemical development and production 11) Patenting and regulatory affairs 12) Clinical trials The Drug Discovery & Development Process 7

8 2. Drug Targets (Receptor or Enzyme) A) PROTEINS Receptors (Agonist or antagonist) Receptors (Agonist or antagonist) Enzymes inhibitor (reversible or irreversible) Enzymes inhibitor (reversible or irreversible) Transporters (Uptake inhibitors) Transporters (Uptake inhibitors) Ion channels (Blockers or openers) Ion channels (Blockers or openers) B) LIPIDS Cell Membrane Lipids (e.g. Polyenes antifungals) Cell Membrane Lipids (e.g. Polyenes antifungals) C) NUCLEIC ACIDS (e.g. alkylating agents) DNA DNA RNA RNA D) CARBOHYDRATES Cell surface carbohydrates Cell surface carbohydrates  An understanding of which biomacromolecules are involved in a particular disease state is clearly important!  This allows the drug designer to identify whether agonists or antagonists should be designed for a particular receptor or whether inhibitors should be designed for a particular enzyme! Drug targets are most often proteins, but nucleic acids may also be attractive targets for some diseases. A bio(macro)molecule may be involved in a disease process, but to be a drug target it has to be validated. In other words shown to be critical in the disease process. 8

9 Between species: (Chemotherapy!) Antibacterial and antiviral agentsAntibacterial and antiviral agents Identify targets which are unique to the invading pathogenIdentify targets which are unique to the invading pathogen Identify targets which are shared but which are significantly different in structureIdentify targets which are shared but which are significantly different in structure Within the body: Selectivity between different enzymes, receptors etc.Selectivity between different enzymes, receptors etc. Selectivity between receptor types and subtypesSelectivity between receptor types and subtypes Selectivity between isozymesSelectivity between isozymes Organ selectivityOrgan selectivity TARGET SELECTIVITY TARGET SELECTIVITY 2. Drug Targets (Receptor or Enzyme) 9

10 Stages: 1) Identify target disease 1) Identify target disease 2) Identify drug target 2) Identify drug target 3) Establish testing procedures 3) Establish testing procedures 4) Find a lead compound 4) Find a lead compound 5) Structure Activity Relationships (SAR) 5) Structure Activity Relationships (SAR) 6) Identify a pharmacophore 6) Identify a pharmacophore 7) Drug design- optimising target interactions 7) Drug design- optimising target interactions 8) Drug design - optimising pharmacokinetic properties 8) Drug design - optimising pharmacokinetic properties 9) Toxicological and safety tests 9) Toxicological and safety tests 10) Chemical development and production 11) Patenting and regulatory affairs 12) Clinical trials The Drug Discovery & Development Process 10

11 Tests are required in order to find lead compounds and for drug optimisationTests are required in order to find lead compounds and for drug optimisation Tests can be in vivo or in vitroTests can be in vivo or in vitro A combination of tests is often used in research programmesA combination of tests is often used in research programmes 3. Establish Testing Procedures 11  Screening or assaying:  “The testing of a (series of) molecule(s) against a known biological target that correlates with a cellular or pharmacological activity is known as screening - e.g. enzyme inhibition or receptor binding”

12 Summary for the first three stages 12  Pharmaceutical companies tend to concentrate on developing drug for diseases that are prevalent in the developed countries, and aim to produce compounds with better properties than existing drugs!  A molecule target is chosen which is believed to influence a particular disease when affected by a drug. The greater the selectivity that can be achieved, the less chance of side effects

13 Stages: 1) Identify target disease 1) Identify target disease 2) Identify drug target 2) Identify drug target 3) Establish testing procedures 3) Establish testing procedures 4) Find a lead compound 4) Find a lead compound 5) Structure Activity Relationships (SAR) 5) Structure Activity Relationships (SAR) 6) Identify a pharmacophore 6) Identify a pharmacophore 7) Drug design- optimising target interactions 7) Drug design- optimising target interactions 8) Drug design - optimising pharmacokinetic properties 8) Drug design - optimising pharmacokinetic properties 9) Toxicological and safety tests 9) Toxicological and safety tests 10) Chemical development and production 11) Patenting and regulatory affairs 12) Clinical trials The Drug Discovery & Development Process 13

14  New projects can be divided into those which have “lead compounds” on which to base the design of novel analogues, and those which do not. 4. Find a lead compound 14  A lead compound is: “a compound from a series of related compounds that has some of a desired biological activity.  This molecule can be characterized, and modified to produce another molecule with a better profile of wanted properties to unwanted side effects”  The level of activity and target selectivity are not crucial  Used as the starting point for drug design and development  A lead compound is a first foothold on the drug discovery ladder  It takes much more effort to make a lead compound into a drug Candidate  Found by design (molecular modelling or NMR) or by screening compounds (natural or synthetic)

15 4.1 Sources of Lead Compounds A) The Natural World B) The Synthetic World C) The Virtual World Plantlife (flowers, trees, bushes) Micro-organisms (bacteria, fungi) Animal life (frogs, snakes, scorpions) Biochemicals (Neurotransmitters, hormones) Marine chemistry (corals, bacteria, fish etc) Chemical synthesis (traditional) Combinatorial synthesis Computer aided drug design 15  Existing drugs can be used as lead compounds for the design of a novel structure in the same therapeutic area.  Alternatively, the side effects of an existing drug can be enhanced to design novel drugs in a different therapeutic area?

16 4.2 Identification of Lead Compounds A) Isolation and purification 1)solvent-solvent extraction (partitioning!) 2)chromatography (TLC, HPLC) 3)crystallisation (based on solubility) 4)distillation (based on differences in boiling point) B) Structure determination 1)NMR ( 1 H, 13 C, 2 D) >>> (structure!) (Functional groups) 2)Mass spectrum >>> (molecular weight or mass) 3)Elemental analysis >>> percentage of different atoms in a molecule) 4)Infra red (IR)>>>(functional groups!) 5)Ultra violet (UV)>>> (absorbance) 16

17 4.1 Sources of Lead Compounds 17  The isolation of many bioactive products from natural sources has led to the systematic screening of plant and animal extracts for activity. Natural product screening Active Principle - a compound that is isolated from a natural extract and which is principally responsible for the extract’s pharmacological activity. Often used as a lead compound.Active Principle - a compound that is isolated from a natural extract and which is principally responsible for the extract’s pharmacological activity. Often used as a lead compound.

18 PLANT EXTRACTS OPIUM - MorphineOPIUM - Morphine CINCHONA BARK - QuinineCINCHONA BARK - Quinine YEW TREE - TaxolYEW TREE - Taxol 4.2.1 Lead Compounds from the Natural World 18 Problems with natural product screening: Isolation of an active component present in a very small amount can be problematic given a large amount of background “rubbish” Isolation of an active component present in a very small amount can be problematic given a large amount of background “rubbish” The mixtures are often very complex and contain many large macromolecules. These can often “hide” biological activity The mixtures are often very complex and contain many large macromolecules. These can often “hide” biological activity Compound isolation and structure determination difficult Compound isolation and structure determination difficult Structures often complex, therefore difficult to synthesise and identify the pharmacophore. Structures often complex, therefore difficult to synthesise and identify the pharmacophore.

19 WILLOW TREE - SALICYLIC ACID COCA BUSH - COCAINE Aspirin Procaine PLANT EXTRACTS 19 4.2.1 Lead Compounds from the Natural World

20 ENDOGENOUS COMPOUNDS NATURAL LIGANDS FOR RECEPTORS Agonist Agonist 20 4.2.1 Lead Compounds from the Natural World 5HT (serotonin natural agonist) 5HT (serotonin agonist) Used for migraine headache (adrenergic natural agonist) (β2 adrenergic agonist) Used for Asthma The natural substrate for a receptor or enzyme can serve as a starting point for lead discovery. E.g. salbutamol, an analogue of the natural compound adrenaline, was developed to treat asthma.

21 Antagonist Antagonist ENDOGENOUS COMPOUNDS NATURAL LIGANDS FOR RECEPTORS 21 4.2.1 Lead Compounds from the Natural World (adrenergic natural agonist) (β adrenergic antagonist) (H2 antagonist)

22 VENOMS AND TOXINS Captopril(anti-hypertensive) Teprotide Lead Compounds from the Natural World 22

23 PRONTOSIL 23 4.2.2 Lead Compounds from the Synthetic World

24 SULFANILAMIDE 24 4.2.2 Lead Compounds from the Synthetic World

25 The Past Lead Compound TargetsTargets Lead compounds The Future Lead Compounds 4.3 Impact of the human genome project 25

26 26 Advances in molecular biology techniques means making and isolating “large” amounts of proteins much easier nowadays. Advances in molecular biology techniques means making and isolating “large” amounts of proteins much easier nowadays. X-ray crystallography has developed so that the determination of the 3-D crystal structures of proteins and receptors is becoming easier. X-ray crystallography has developed so that the determination of the 3-D crystal structures of proteins and receptors is becoming easier. Coupled with advances in computing power and molecular modelling the so- called rational or structure-based drug design hasbeen advanced as “the way forward” in the search for new drugs. Coupled with advances in computing power and molecular modelling the so- called rational or structure-based drug design hasbeen advanced as “the way forward” in the search for new drugs. 4.4 Lead Compounds - Rational drug design (molecular modelling) The ability to crystallise a molecular target allows the use of X-ray crystallography and molecular modelling to design lead compounds which fit the relevant binding site

27 PROTEIN STRUCTURE 27 4.4 Lead Compounds - de novo design (molecular modelling) (molecular modelling) The ability to crystallise a molecular target allows the use of X-ray crystallography and molecular modelling to design lead compounds which fit the relevant binding site

28 The Design of Relenza ( influenza neuraminidase inhibitor) Relenza bound in the active site of influenza neuraminidase  Neuraminidase is an enzyme involved in the influenza virus cycle.  A screen of inhibitors of neuraminidase came up with a hit which was developed into a lead compound.  The X-ray crystal structure of the virus enzyme is known so a computational study has allowed the “docking” (superposition) of the lead structure into the active site of the enzyme.  This study is directing optimization of the inhibitor structure through determination of the intermolecular forces between enzyme and inhibitor.

29 Important interactions between the guanidino group and influenza neuraminidase The Design of Relenza

30 Stages: 1) Identify target disease 1) Identify target disease 2) Identify drug target 2) Identify drug target 3) Establish testing procedures 3) Establish testing procedures 4) Find a lead compound 4) Find a lead compound 5) Structure Activity Relationships (SAR) 5) Structure Activity Relationships (SAR) 6) Identify a pharmacophore 6) Identify a pharmacophore 7) Drug design- optimising target interactions 7) Drug design- optimising target interactions 8) Drug design - optimising pharmacokinetic properties 8) Drug design - optimising pharmacokinetic properties 9) Toxicological and safety tests 9) Toxicological and safety tests 10) Chemical development and production 11) Patenting and regulatory affairs 12) Clinical trials The Drug Discovery & Development Process 30

31 5 & 6 Structure Activity Relationships (SAR) & Identifying Pharmacophore Alter, remove or mask a functional group Alter, remove or mask a functional group Test the analogue for activityTest the analogue for activity Conclusions depend on the method of testingConclusions depend on the method of testing  in vitro - tests for binding interactions with target  in vivo - tests for target binding interactions and/or pharmacokinetics AIM - Identify which functional groups are important for binding and/or activity METHOD 31  We have defined a lead compound as “a compound from a series of related compounds…...”. The question is therefore posed what are the essential structural elements for biological activity? >> (pharmacophore) Defines the important groups involved in binding Defines the important groups involved in binding Defines the relative positions of the binding groupsDefines the relative positions of the binding groups Need to know Active ConformationNeed to know Active Conformation

32 32  Once a pharmacophore has been identified as series of related compounds must be made to improve potency and reduce toxicity  Determination of a structure-activity relationship (SAR) is the process by which chemical structure is correlated with biological Activity 5 & 6 Structure Activity Relationships (SAR) & Identifying Pharmacophore

33 Stages: 1) Identify target disease 1) Identify target disease 2) Identify drug target 2) Identify drug target 3) Establish testing procedures 3) Establish testing procedures 4) Find a lead compound 4) Find a lead compound 5) Structure Activity Relationships (SAR) 5) Structure Activity Relationships (SAR) 6) Identify a pharmacophore 6) Identify a pharmacophore 7) Drug design- optimising target interactions 7) Drug design- optimising target interactions 8) Drug design - optimising pharmacokinetic properties 8) Drug design - optimising pharmacokinetic properties 9) Toxicological and safety tests 9) Toxicological and safety tests 10) Chemical development and production 11) Patenting and regulatory affairs 12) Clinical trials The Drug Discovery & Development Process 33

34 7. DRUG DESIGN - OPTIMISING BINDING INTERACTIONS AIM - To optimise binding interactions with target STRATEGIES Vary alkyl substituentsVary alkyl substituents Vary aryl substituentsVary aryl substituents ExtensionExtension Chain extensions / contractionsChain extensions / contractions Ring expansions / contractionsRing expansions / contractions Ring variationRing variation IsosteresIsosteres SimplificationSimplification RigidificationRigidification To increase activity and reduce dose levels To increase activity and reduce dose levels To increase selectivity and reduce side effects To increase selectivity and reduce side effects REASONS 34

35 7.1 Vary Alkyl Substituents Rationale : Alkyl group in lead compound may interact with hydrophobicAlkyl group in lead compound may interact with hydrophobic region in binding site Vary length and bulk of group to optimise interactionVary length and bulk of group to optimise interaction 35

36 Rationale : Vary length and bulk of alkyl group to introduce selectivity Binding region for N Receptor 1 Receptor 2 36 7.1 Vary Alkyl Substituents Example: Next.... Selectivity of adrenergic agonists and antagonists for  - adrenoceptors over  -adrenoceptors

37 Salbutamol(Ventolin)(Anti-asthmatic) Adrenaline Propranolol (  -Blocker) 37 7.1 Vary Alkyl Substituents

38 RECEPTOR Rationale : To explore target binding site for further binding regions to achieve additional binding interactions 7.2 Extension - Extra Functional Groups Unusedbindingregion DRUG RECEPTOR DRUG Extrafunctionalgroup Binding regions Binding group DrugExtension 38

39 Example : ACE Inhibitors EXTENSION Hydrophobic pocket Bindingsite Bindingsite Vacant 39 7.2 Extension - Extra Functional Groups

40 Rationale : Useful if a chain is present connecting two binding groupsUseful if a chain is present connecting two binding groups Vary length of chain to optimise interactionsVary length of chain to optimise interactions 7.3 Chain Extension / Contraction RECEPTOR A B A B RECEPTOR Binding regions Binding groups A & B Weakinteraction Stronginteraction Chainextension 40

41 Bindinggroup Bindinggroup Example : N-Phenethylmorphine Optimum chain length = 2 41 7.3 Chain Extension / Contraction

42 7.4 Ring Variations Example : Improved selectivity vs. fungal enzyme Antifungal agent Ringvariation 42 Rationale : Sometimes results in improved properties

43 Rationale : Lead compounds from natural sources are often complex and difficult to synthesiseLead compounds from natural sources are often complex and difficult to synthesise Simplifying the molecule makes synthesis of analogues easier, quicker and cheaperSimplifying the molecule makes synthesis of analogues easier, quicker and cheaper Simpler structures may fit binding site easier and increase activitySimpler structures may fit binding site easier and increase activity Simpler structures may be more selective and less toxic if excess functional groups removedSimpler structures may be more selective and less toxic if excess functional groups removed 7.5 Simplification 43

44 Methods: Retain pharmacophoreRetain pharmacophore Remove unnecessary functional groupsRemove unnecessary functional groups 44 7.5 Simplification

45 Excess ring Methods : Remove excess ringsRemove excess ringsExample Excess functional groups 45 7.5 Simplification

46 Methods: Remove asymmetric centresRemove asymmetric centres 46 7.5 Simplification

47 Pharmacophore Example Important binding groups retainedImportant binding groups retained Unnecessary ester removedUnnecessary ester removed Complex ring system removedComplex ring system removed 47 7.5 Simplification

48 48 7.5 Simplification Disadvantages: Oversimplification may result in decreased activity and selectivityOversimplification may result in decreased activity and selectivity Simpler molecules have more conformationsSimpler molecules have more conformations More likely to interact with more than one target binding site.More likely to interact with more than one target binding site.

49 MORPHINE SIMPLIFICATION C C C C C C O N 49 7.5 Simplification Example of oversimplification Simplification of opiates

50 7.6 De Novo Drug Design Procedure Crystallise target protein with bound ligandCrystallise target protein with bound ligand (e.g. enzyme + inhibitor or ligand) (e.g. enzyme + inhibitor or ligand) Acquire structure by X-ray crystallographyAcquire structure by X-ray crystallography Identify binding site (region where ligand is bound)Identify binding site (region where ligand is bound) Remove ligandRemove ligand Identify potential binding regions in the binding siteIdentify potential binding regions in the binding site Design a lead compound to interact with the binding siteDesign a lead compound to interact with the binding site Synthesise the lead compound and test it for activitySynthesise the lead compound and test it for activity Crystallise the lead compound with target protein and identify the actual binding interactionsCrystallise the lead compound with target protein and identify the actual binding interactions Structure based drug designStructure based drug design 50  The design of novel agents based on a knowledge of the target binding site

51 Stages: 1) Identify target disease 1) Identify target disease 2) Identify drug target 2) Identify drug target 3) Establish testing procedures 3) Establish testing procedures 4) Find a lead compound 4) Find a lead compound 5) Structure Activity Relationships (SAR) 5) Structure Activity Relationships (SAR) 6) Identify a pharmacophore 6) Identify a pharmacophore 7) Drug design- optimising target interactions 7) Drug design- optimising target interactions 8) Drug design - optimising pharmacokinetic properties 8) Drug design - optimising pharmacokinetic properties 9) Toxicological and safety tests 9) Toxicological and safety tests 10) Chemical development and production 11) Patenting and regulatory affairs 12) Clinical trials The Drug Discovery & Development Process 51

52 8. Pharmacokinetics – drug design Aims: To improve pharmacokinetic properties of lead compoundTo improve pharmacokinetic properties of lead compound To optimise chemical and metabolic stability (stomach acids / digestive enzymes / metabolic enzymes)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)To optimise hydrophilic / hydrophobic balance (solubility in blood / solubility in GIT / solubility through cell membranes / access to CNS / excretion rate) 52

53 Drugs must be polar - to be soluble in aqueous conditions - to interact with molecular targetsDrugs 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 excretionDrugs must be ‘fatty’ - to cross cell membranes - to avoid rapid excretion Drugs must have both hydrophilic and lipophilic characteristicsDrugs must have both hydrophilic and lipophilic characteristics Many drugs are weak bases with pK a ’s 6-8Many drugs are weak bases with pK a ’s 6-8 53 8. Pharmacokinetics – drug design

54 8.1.1 Vary alkyl substituents Rationale: Varying the size of alkyl groups varies the hydrophilic / hydrophobic balance of the structureVarying the size of alkyl groups varies the hydrophilic / hydrophobic balance of the structure Larger alkyl groups increase hydrophobicityLarger alkyl groups increase hydrophobicity Disadvantage: May interfere with target binding for steric reasonsMay interfere with target binding for steric reasons Methods: Often feasible to remove alkyl groups from heteroatoms and replace with different alkyl groupsOften feasible to remove alkyl groups from heteroatoms and replace with different alkyl groups Usually difficult to remove alkyl groups from the carbon skeleton - full synthesis often requiredUsually difficult to remove alkyl groups from the carbon skeleton - full synthesis often required 8.1 Solubility and membrane permeability 54

55 8.1.1 Vary alkyl substituents Methylene Shuffle Extra bulk 55 8.1 Solubility and membrane permeability

56 8.1.2 ‘Masking’ or removing polar groups Rationale: Masking or removing polar groups decreases polarity and increases hydrophobic characterMasking or removing polar groups decreases polarity and increases hydrophobic characterDisadvantages: Polar group may be involved in target bindingPolar group may be involved in target binding Unnecessary polar groups are likely to have been removed already (simplification strategy)Unnecessary polar groups are likely to have been removed already (simplification strategy) See also prodrugsSee also prodrugsMethods: 56 8.1 Solubility and membrane permeability

57 1.1.3 Adding polar groups Rationale: Adding polar groups increases polarity and decreases hydrophobic characterAdding polar groups increases polarity and decreases hydrophobic character Useful for targeting drugs vs. gut infectionsUseful for targeting drugs vs. gut infections Useful for reducing CNS side effectsUseful for reducing CNS side effects Disadvantage: May introduce unwanted side effectsMay introduce unwanted side effects Antifungal agent with poor solubility - skin infections only solubility - skin infections only Systemic antifungal agent improved blood solubility 57 8.1 Solubility and membrane permeability

58 8.1.4 Vary pK a Rationale: Varying pK a alters percentage of drug which is ionisedVarying pK a alters percentage of drug which is ionised Alter pK a to obtain required ratio of ionised to unionised drugAlter pK a to obtain required ratio of ionised to unionised drug Disadvantage: May affect binding interactionsMay affect binding interactions Method: Vary alkyl substituents on amine nitrogensVary alkyl substituents on amine nitrogens Vary aryl substituents to influence aromatic amines or aromatic carboxylic acidsVary aryl substituents to influence aromatic amines or aromatic carboxylic acids 58 8.1 Solubility and membrane permeability

59 Antithrombotic but too basic Decreased basicity N locked into heterocycle 59 8.1.4 Vary pK a 8.1 Solubility and membrane permeability

60 Terminal amide StericShield 8.2.1 Steric Shields Rationale: Used to increase chemical and metabolic stabilityUsed to increase chemical and metabolic stability Introduce bulky group as a shieldIntroduce bulky group as a shield Protects a susceptible functional group (e.g. ester) from hydrolysisProtects a susceptible functional group (e.g. ester) from hydrolysis Hinders attack by nucleophiles or enzymesHinders attack by nucleophiles or enzymes Blocks hydrolysis of terminal amide Antirheumatic agent D1927 60 8.2 Drug stability

61 8.2.2 ‘Electronic shielding’ of NH 2 Rationale: Used to stabilise labile functional groups (e.g. esters)Used to stabilise labile functional groups (e.g. esters) Replace labile ester with more stable urethane or amideReplace labile ester with more stable urethane or amide Nitrogen feeds electrons into carbonyl group and makes it less reactiveNitrogen feeds electrons into carbonyl group and makes it less reactive Increases chemical and metabolic stabilityIncreases chemical and metabolic stability 61 8.2 Drug stability

62 8.2.3 Stereoelectronic Effects Rationale: Steric and electronic effects used in combinationSteric and electronic effects used in combination Increases chemical and metabolic stabilityIncreases chemical and metabolic stability ortho Methyl groups act as steric shields & hinder hydrolysis by esterases Amide more stable than ester (electronic effect) Local anaesthetic (short duration) 8.2 Drug stability 62

63 Rationale: Metabolism of drugs usually occur at specific sites. Introduce groups at a susceptible site to block the reactionMetabolism of drugs usually occur at specific sites. Introduce groups at a susceptible site to block the reaction Increases metabolic stability and drug lifetimeIncreases metabolic stability and drug lifetime Oral contraceptive - limited lifetime - limited lifetime 8.2.5 Metabolic blockers 63 8.2 Drug stability

64 Rationale: Metabolism of drugs usually occurs at specific groups.Metabolism of drugs usually occurs at specific groups. Remove susceptible group or replace it with metabolically stable group [ e.g. modification of tolbutamide (antibiotic)]Remove susceptible group or replace it with metabolically stable group [ e.g. modification of tolbutamide (antibiotic)]Susceptiblegroup Unsusceptiblegroup 8.2.6 Remove / replace susceptible metabolic groups TOLBUTAMIDE Rapidly excreted - short lifetime 64 8.2 Drug stability

65 Rationale: Used if the metabolically susceptible group is important for bindingUsed if the metabolically susceptible group is important for binding Shift its position to make it unrecognisable to metabolic enzymeShift its position to make it unrecognisable to metabolic enzyme Must still be recognisable to targetMust still be recognisable to targetExample:SalbutamolSusceptiblegroup Unsusceptiblegroup 8.2.7 Shifting susceptible metabolic groups 65 8.2 Drug stability

66 Rationale: Used to decrease metabolic stability and drug lifetimeUsed to decrease metabolic stability and drug lifetime Used for drugs which ‘linger’ too long in the body and cause side effectsUsed for drugs which ‘linger’ too long in the body and cause side effects Add groups known to be susceptible to Phase I or Phase II metabolic reactionsAdd groups known to be susceptible to Phase I or Phase II metabolic reactions Example: Anti-arthritic agents 1.2.8 Introducing susceptible metabolic groups 66 8.2 Drug stability

67 Example - varying substituents Fluconazole (Diflucan) - antifungal agentFluconazole (Diflucan) - antifungal agent Substituents varied Less toxic 8.3 Reducing drug toxicity 67

68 Example - varying substituent position Dopamine antagonistsDopamine antagonists Inhibits P450 enzymes No inhibition of P450 enzymes 68 8.3 Reducing drug toxicity

69 Stages: 1) Identify target disease 1) Identify target disease 2) Identify drug target 2) Identify drug target 3) Establish testing procedures 3) Establish testing procedures 4) Find a lead compound 4) Find a lead compound 5) Structure Activity Relationships (SAR) 5) Structure Activity Relationships (SAR) 6) Identify a pharmacophore 6) Identify a pharmacophore 7) Drug design- optimising target interactions 7) Drug design- optimising target interactions 8) Drug design - optimising pharmacokinetic properties 8) Drug design - optimising pharmacokinetic properties 9) Toxicological and safety tests 9) Toxicological and safety tests 10) Chemical development and production 11) Patenting and regulatory affairs 12) Clinical trials The Drug Discovery & Development Process 69

70 Pro-drugs 70

71 Definition: Inactive compounds which are converted to active compounds in the body. Uses...Aims.....(improving drug profile!) Improving membrane permeabilityImproving membrane permeability Prolonging activityProlonging activity Masking toxicity and side effectsMasking toxicity and side effects Varying water solubilityVarying water solubility Drug targetingDrug targeting Improving chemical stabilityImproving chemical stability 8.5 Prodrugs 71

72 8.5.1 Prodrugs to improve membrane permeability 8.5.1.1 Esters Used to mask polar and ionisable carboxylic acidsUsed to mask polar and ionisable carboxylic acids Hydrolysed in blood by esterasesHydrolysed in blood by esterases Used when a carboxylic acid is required for target bindingUsed when a carboxylic acid is required for target binding Leaving group (alcohol) should ideally be non toxicLeaving group (alcohol) should ideally be non toxic Example: Enalapril for enalaprilate (antihypertensive) 72

73 Example: Candoxatril for Candoxatrilat (protease inhibitor) Varying the ester varies the rate of hydrolysisVarying the ester varies the rate of hydrolysis Electron withdrawing groups increase rate of hydrolysisElectron withdrawing groups increase rate of hydrolysis (e.g. 5-indanyl) Leaving group (5-indanol) is non toxicLeaving group (5-indanol) is non toxic 73 8.5.1 Prodrugs to improve membrane permeability

74 8.5.1.2 N-Methylation of amines Used to reduce polarity of aminesUsed to reduce polarity of amines Demethylated in liverDemethylated in liver Example:Hexobarbitone 74 8.5.1 Prodrugs to improve membrane permeability

75 Dopamine Useful in treating Parkinson’s DiseaseUseful in treating Parkinson’s Disease Too polar to cross cell membranes and BBBToo polar to cross cell membranes and BBB Levodopa More polar but is an amino acidMore polar but is an amino acid Carried across cell membranes by carrier proteins for amino acidsCarried across cell membranes by carrier proteins for amino acids Decarboxylated in cell to dopamineDecarboxylated in cell to dopamine 8.5.1.3 Trojan Horse Strategy Prodrug designed to mimic biosynthetic building blockProdrug designed to mimic biosynthetic building block Transported across cell membranes by carrier proteinsTransported across cell membranes by carrier proteins Example: Levodopa for dopamine 75 8.5.1 Prodrugs to improve membrane permeability

76 COOH H2NH2NH2NH2N L-Dopa COOH H2NH2NH2NH2N Enzyme Dopamine H2NH2NH2NH2N BloodsupplyBraincells BLOOD BRAIN BARRIER 76 8.5.1 Prodrugs to improve membrane permeability

77 Example: Azathioprine for 6-mercaptopurine 6-Mercaptopurine (suppresses immune response) Short lifetime - eliminated too quicklyShort lifetime - eliminated too quickly Azathioprine Slow conversion to 6-mercaptopurineSlow conversion to 6-mercaptopurine Longer lifetimeLonger lifetime 8.5.2 Prodrugs to prolong activity 77 8.5.2.1 Mask polar groups Reduces rate of excretionReduces rate of excretion

78 Example: Valium for nordazepam Valium for nordazepam Valium Nordazepam N-Demethylation 78 8.5.2 Prodrugs to prolong activity

79 Example: Hydrophobic esters of fluphenazine (antipsychotic) Hydrophobic esters of fluphenazine (antipsychotic) Given by intramuscular injectionGiven by intramuscular injection Concentrated in fatty tissueConcentrated in fatty tissue Slowly released into the blood supplySlowly released into the blood supply Rapidly hydrolysed in the blood supplyRapidly hydrolysed in the blood supply 79 8.5.2 Prodrugs to prolong activity 8.5.2.2 Add hydrophobic groups

80 Example: Aspirin for salicylic acid 8.5.3 Prodrugs to mask toxicity and side effects Salicylic acid Analgesic, but causes stomachAnalgesic, but causes stomach ulcers due to phenol group Aspirin Phenol masked by esterPhenol masked by ester Hydrolysed in bodyHydrolysed in body 80 Mask groups responsible for toxicity/side effectsMask groups responsible for toxicity/side effects Used when groups are important for activityUsed when groups are important for activity

81 8.5.4 Prodrugs to lower water solubility Example: Palmitate ester of chloramphenicol (antibiotic) Palmitate ester Esterase Chloramphenicol 81 Used to reduce solubility of foul tasting orally active drugsUsed to reduce solubility of foul tasting orally active drugs Less soluble on tongueLess soluble on tongue Less revolting tasteLess revolting taste

82 8.5.5 Prodrugs to increase water solubility Succinate ester Esterase Chloramphenicol 82 Often used for i.v. drugsOften used for i.v. drugs Allows higher concentration and smaller dose volumeAllows higher concentration and smaller dose volume May decrease pain at site of injectionMay decrease pain at site of injection Example: Succinate ester of chloramphenicol (antibiotic

83 Example: Phosphate ester of clindamycin (antibacterial) Less painful on injectionLess painful on injection 83 8.5.5 Prodrugs to increase water solubility

84 8.5.6 Prodrugs to increase chemical stability Example: Hetacillin for ampicillin Ampicillin is chemically unstable in solution due to the  - NH 2 group attacking the  -lactase ringAmpicillin is chemically unstable in solution due to the  - NH 2 group attacking the  -lactase ring ‘N’ in heteracillin is locked up within a heterocyclic ring‘N’ in heteracillin is locked up within a heterocyclic ring 84

85 Definition: A drug that is added to ‘protect’ another drug Example:Carbidopa Carbidopa protects L-dopaCarbidopa protects L-dopa It inhibits the decarboxylase enzyme in the peripheral blood supplyIt inhibits the decarboxylase enzyme in the peripheral blood supply It is polar and does not cross the blood brain barrierIt is polar and does not cross the blood brain barrier It has no effect on the decarboxylation of L-Dopa in the CNSIt has no effect on the decarboxylation of L-Dopa in the CNS Smaller doses of L-dopa can be administered - less side effectsSmaller doses of L-dopa can be administered - less side effects 8.6.1 Sentry Drugs Other examples: Clavulanic acid and candoxatril 85

86 Example: Adrenaline and procaine (local anaesthetic) Adrenaline constricts blood vessels at the injection areaAdrenaline constricts blood vessels at the injection area Procaine is localised at the injection areaProcaine is localised at the injection area 8.6.2 Localising drugs to a target area 8.6.3 Increasing absorption Administered with analgesics in the treatment of migraineAdministered with analgesics in the treatment of migraine Increases gastric motility and causes faster absorption of analgesicsIncreases gastric motility and causes faster absorption of analgesics Leads to faster pain reliefLeads to faster pain relief Example: Metoclopramide 86

87 Structure based drug design Procedure: Crystallise target protein with bound ligand (e.g. enzyme + inhibitor or ligand)Crystallise target protein with bound ligand (e.g. enzyme + inhibitor or ligand) Acquire structure by X-ray crystallographyAcquire structure by X-ray crystallography Identify binding site (region where ligand is bound)Identify binding site (region where ligand is bound) Identify binding interactions between ligand and target (modelling)Identify binding interactions between ligand and target (modelling) Identify vacant regions for extra binding interactions (modelling)Identify vacant regions for extra binding interactions (modelling) ‘Fit’ analogues into binding site to test binding capability (modelling)‘Fit’ analogues into binding site to test binding capability (modelling) 87 Strategy: Carry out drug design based on the interactions between the lead compound and the target binding site

88 Stages: 1) Identify target disease 1) Identify target disease 2) Identify drug target 2) Identify drug target 3) Establish testing procedures 3) Establish testing procedures 4) Find a lead compound 4) Find a lead compound 5) Structure Activity Relationships (SAR) 5) Structure Activity Relationships (SAR) 6) Identify a pharmacophore 6) Identify a pharmacophore 7) Drug design- optimising target interactions 7) Drug design- optimising target interactions 8) Drug design - optimising pharmacokinetic properties 8) Drug design - optimising pharmacokinetic properties 9) Toxicological and safety tests 9) Toxicological and safety tests 10) Chemical development and production 11) Patenting and regulatory affairs 12) Clinical trials The Drug Discovery & Development Process 88

89  Drug Metabolism Identification of drug metabolites in test animals Properties of drug metabolites  Toxicology In vivo and in vitro tests for acute and chronic toxicity  Pharmacology Selectivity of action at drug target  Formulation Stability tests Methods of delivery 9.1 Preclinical trials

90 Stages: 1) Identify target disease 1) Identify target disease 2) Identify drug target 2) Identify drug target 3) Establish testing procedures 3) Establish testing procedures 4) Find a lead compound 4) Find a lead compound 5) Structure Activity Relationships (SAR) 5) Structure Activity Relationships (SAR) 6) Identify a pharmacophore 6) Identify a pharmacophore 7) Drug design- optimising target interactions 7) Drug design- optimising target interactions 8) Drug design - optimising pharmacokinetic properties 8) Drug design - optimising pharmacokinetic properties 9) Toxicological and safety tests 9) Toxicological and safety tests 10) Chemical development and production 11) Patenting and regulatory affairs 12) Clinical trials The Drug Discovery & Development Process 90

91 91 Case Study - Development of Design of Antihypertensives - ACE inhibitors

92 ACE = Angiotensin converting enzymeACE = Angiotensin converting enzyme Angiotensin II - hormone which stimulates constriction of blood vessels - causes rise in blood pressureAngiotensin II - hormone which stimulates constriction of blood vessels - causes rise in blood pressure ACE inhibitors - useful antihypertensive agentsACE inhibitors - useful antihypertensive agents ACE - membrane bound zinc metalloproteinase not easily crystallisedACE - membrane bound zinc metalloproteinase not easily crystallised Study analogous enzyme which can be crystallisedStudy analogous enzyme which can be crystallised 92 Structure based drug design Design of Antihypertensives - ACE inhibitors

93 Hydrolysis 93 Structure based drug design Carboxypeptidase mechanism

94 No hydrolysis 94 Structure based drug design Inhibition of carboxypeptidase

95 95 Structure based drug design Lead compounds for ACE inhibitor

96 Proposed binding mode 96 Structure based drug design

97 Extension and bio-isostere strategies 97 Structure based drug design

98 Extension strategies 98 Structure based drug design


Download ppt "1 MEDICINAL CHEMISTRY I (PharmD) 2012 Topic 3: Drug Design and Discovery Dr. Tareq Abu-Izneid & Dr. Munjed Ibrahim"

Similar presentations


Ads by Google