MEDICINAL CHEMISTRY I (PharmD) 2012

MEDICINAL CHEMISTRY I (PharmD) 2012
Topic 4: Drug Design and Discovery 14/04/2017 MEDICINAL CHEMISTRY I (PharmD) 2012 Topic 3: Drug Design and Discovery Dr. Tareq Abu-Izneid & Dr. Munjed Ibrahim Dr Tareq Abu-Izneid

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

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

The Drug Discovery & Development Process

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 tests 10) Chemical development and production 11) Patenting and regulatory affairs 12) Clinical trials

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? Questions to be addressed Is the disease widespread? (e.g. cardiovascular disease, ulcers, malaria) Does the disease affect the first world? (e.g. cardiovascular disease, ulcers) Are there drugs already on the market? If so, what are there advantages and disadvantages? (e.g. side effects) Can one identify a market advantage for a new therapy? Choosing which disease to tackle is a matter for a company’s market strategists!!

2. Drug Targets (Receptor or Enzyme)
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! A) PROTEINS Receptors (Agonist or antagonist) Enzymes inhibitor (reversible or irreversible) Transporters (Uptake inhibitors) Ion channels (Blockers or openers) B) LIPIDS Cell Membrane Lipids (e.g. Polyenes antifungals) C) NUCLEIC ACIDS (e.g. alkylating agents) DNA RNA D) CARBOHYDRATES Cell surface carbohydrates 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. Drug targets are most often proteins, but nucleic acids may also be attractive targets for some diseases.

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

3. Establish Testing Procedures
Tests are required in order to find lead compounds and for drug optimisation Tests can be in vivo or in vitro A combination of tests is often used in research programmes 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”

Summary for the first three stages
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

4. Find a lead compound 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. 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)

4.1 Sources of Lead Compounds
Plantlife (flowers, trees, bushes) Micro-organisms (bacteria, fungi) Animal life (frogs, snakes, scorpions) Biochemicals (Neurotransmitters, hormones) Marine chemistry (corals, bacteria, fish etc) A) The Natural World Chemical synthesis (traditional) Combinatorial synthesis B) The Synthetic World Computer aided drug design C) The Virtual World 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?

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

4.1 Sources of Lead Compounds
Natural product screening The isolation of many bioactive products from natural sources has led to the systematic screening of plant and animal extracts for activity. 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.

4.2.1 Lead Compounds from the Natural World
PLANT EXTRACTS OPIUM - Morphine CINCHONA BARK - Quinine YEW TREE - Taxol 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” • The mixtures are often very complex and contain many large macromolecules. These can often “hide” biological activity • Compound isolation and structure determination difficult • Structures often complex, therefore difficult to synthesise and identify the pharmacophore.

PLANT EXTRACTS WILLOW TREE - SALICYLIC ACID Aspirin COCA BUSH - COCAINE Procaine

ENDOGENOUS COMPOUNDS NATURAL LIGANDS FOR RECEPTORS 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. Agonist (adrenergic natural agonist) (β2 adrenergic agonist) Used for Asthma Agonist 5HT (serotonin natural agonist) 5HT (serotonin agonist) Used for migraine headache

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

Lead Compounds from the Natural World
VENOMS AND TOXINS Teprotide MOR008C.WAV Teprotide was chosen as a lead because of its long-lasting in vivo activity. This was demonstrated by Bianchi et al.[4] by administering teprotide to dogs and rats and observing that it inhibited the vasopressor response induced by angiotensin I. Teprotide was shown to be an effective antihypertension agent but it had limited use because of its expense and lack of oral activity. It was found that teprotide inhibits the enzyme that converts angiotensin I to angiotensin II. From this researchers conducted structure-activity studies which allowed them to identify the active binding site of the ACE which allowed for the development of antihypertension drugs to be developed. Captopril was the first antihypertension drug developed by Ondetti and Cushman.[5] Many ACE inhibitors have been developed since this time but this was the start of them. Captopril (anti-hypertensive)

4.2.2 Lead Compounds from the Synthetic World
PRONTOSIL

4.2.2 Lead Compounds from the Synthetic World
SULFANILAMIDE

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

4.4 Lead Compounds - Rational drug design (molecular modelling)
• 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. • 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. 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

4.4 Lead Compounds - de novo design (molecular modelling)
PROTEIN STRUCTURE 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

The Design of Relenza (influenza neuraminidase inhibitor)
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. Relenza bound in the active site of influenza neuraminidase

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

5 & 6 Structure Activity Relationships (SAR) &
Identifying Pharmacophore AIM - Identify which functional groups are important for binding and/or activity Alter, remove or mask a functional group Test the analogue for activity Conclusions depend on the method of testing in vitro - tests for binding interactions with target in vivo - tests for target binding interactions and/or pharmacokinetics METHOD 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 relative positions of the binding groups Need to know Active Conformation

5 & 6 Structure Activity Relationships (SAR) &
Identifying Pharmacophore 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

AIM - To optimise binding interactions with target
7. DRUG DESIGN - OPTIMISING BINDING INTERACTIONS AIM - To optimise binding interactions with target To increase activity and reduce dose levels To increase selectivity and reduce side effects REASONS STRATEGIES Vary alkyl substituents Vary aryl substituents Extension Chain extensions / contractions Ring expansions / contractions Ring variation Isosteres Simplification Rigidification

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

Rationale : Vary length and bulk of alkyl group to introduce selectivity Binding region for N Receptor 1 Receptor 2 Example: Next.... Selectivity of adrenergic agonists and antagonists for b-adrenoceptors over a-adrenoceptors

Adrenaline Salbutamol (Ventolin) (Anti-asthmatic) Propranolol (b-Blocker)

7.2 Extension - Extra Functional Groups
Rationale : To explore target binding site for further binding regions to achieve additional binding interactions RECEPTOR RECEPTOR Extra functional group Unused binding region DRUG DRUG Drug Extension Binding regions Binding group

7.2 Extension - Extra Functional Groups
Example : ACE Inhibitors Hydrophobic pocket Vacant EXTENSION Hydrophobic pocket Binding site Binding site

7.3 Chain Extension / Contraction
Rationale : Useful if a chain is present connecting two binding groups Vary length of chain to optimise interactions Weak interaction Strong interaction A B Chain extension A B RECEPTOR RECEPTOR Binding regions Binding groups A & B

7.3 Chain Extension / Contraction
Example : N-Phenethylmorphine Binding group Optimum chain length = 2

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

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

Remove unnecessary functional groups
7.5 Simplification Methods: Retain pharmacophore Remove unnecessary functional groups

7.5 Simplification Methods: Example Remove excess rings
Excess functional groups Excess ring

7.5 Simplification Methods: Remove asymmetric centres

Example 7.5 Simplification Important binding groups retained
Pharmacophore Important binding groups retained Unnecessary ester removed Complex ring system removed

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

7.5 Simplification MORPHINE SIMPLIFICATION
Example of oversimplification Simplification of opiates C C O C C C C MOR062.WAV N SIMPLIFICATION

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

8. Pharmacokinetics – drug design
Aims: 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)

8. Pharmacokinetics – drug design
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

8.1 Solubility and membrane permeability
8.1.1 Vary alkyl substituents Rationale: Varying the size of alkyl groups varies the hydrophilic / hydrophobic balance of the structure Larger alkyl groups increase hydrophobicity Disadvantage: May interfere with target binding for steric reasons Methods: Often 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 required

8.1.1 Vary alkyl substituents Methylene Shuffle Extra bulk

8.1.2 ‘Masking’ or removing polar groups Rationale: Masking or removing polar groups decreases polarity and increases hydrophobic character Disadvantages: Polar group may be involved in target binding Unnecessary polar groups are likely to have been removed already (simplification strategy) See also prodrugs Methods:

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

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

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

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

8.2 Drug stability 8.2.2 ‘Electronic shielding’ of NH2 Rationale:
Used to stabilise labile functional groups (e.g. esters) Replace labile ester with more stable urethane or amide Nitrogen feeds electrons into carbonyl group and makes it less reactive Increases chemical and metabolic stability

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

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

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

8.2 Drug stability 8.2.7 Shifting susceptible metabolic groups
Rationale: Used if the metabolically susceptible group is important for binding Shift its position to make it unrecognisable to metabolic enzyme Must still be recognisable to target Example: Salbutamol Unsusceptible group Susceptible group

8.2 Drug stability 1.2.8 Introducing susceptible metabolic groups
Rationale: Used to decrease metabolic stability and drug lifetime Used 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 reactions Example: Anti-arthritic agents

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

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

Pro-drugs

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

8.5.1 Prodrugs to improve membrane permeability
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 toxic Example: Enalapril for enalaprilate (antihypertensive)

Example: Candoxatril for Candoxatrilat (protease inhibitor) Varying the ester varies the rate of hydrolysis Electron withdrawing groups increase rate of hydrolysis (e.g. 5-indanyl) Leaving group (5-indanol) is non toxic

N-Methylation of amines Used to reduce polarity of amines Demethylated in liver Example: Hexobarbitone

Trojan Horse Strategy Prodrug designed to mimic biosynthetic building block Transported across cell membranes by carrier proteins Example: Levodopa for dopamine Dopamine Useful in treating Parkinson’s Disease Too polar to cross cell membranes and BBB Levodopa More polar but is an amino acid Carried across cell membranes by carrier proteins for amino acids Decarboxylated in cell to dopamine

Blood supply Brain cells BLOOD BRAIN BARRIER COOH H2N COOH H2N L-Dopa Enzyme Dopamine H2N

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

Example: Valium for nordazepam Valium Nordazepam N-Demethylation

Add hydrophobic groups Example: Hydrophobic esters of fluphenazine (antipsychotic) Given by intramuscular injection Concentrated in fatty tissue Slowly released into the blood supply Rapidly hydrolysed in the blood supply

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

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

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

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

8.5.6 Prodrugs to increase chemical stability
Example: Hetacillin for ampicillin Ampicillin is chemically unstable in solution due to the a-NH2 group attacking the b-lactase ring ‘N’ in heteracillin is locked up within a heterocyclic ring

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

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

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

9.1 Preclinical trials 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

Case Study - Development of Design of Antihypertensives - ACE inhibitors

Design of Antihypertensives - ACE inhibitors ACE = Angiotensin converting enzyme Angiotensin II hormone which stimulates constriction of blood vessels - causes rise in blood pressure ACE inhibitors - useful antihypertensive agents ACE - membrane bound zinc metalloproteinase not easily crystallised Study analogous enzyme which can be crystallised

Carboxypeptidase mechanism Hydrolysis

Inhibition of carboxypeptidase No hydrolysis

Lead compounds for ACE inhibitor

Proposed binding mode

Extension and bio-isostere strategies

Extension strategies

MEDICINAL CHEMISTRY I (PharmD) 2012

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