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OPTIMIZING DRUG PROPERTIES LEAD-TO-DRUG DESIGN
Presentation · March 2019
DOI: 10.13140/RG.2.2.14867.12322
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Samer Housheh
Wadi International University
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3/26/2019
Al-Andalus University for Medical Sciences
Faculty of Pharmacy
OPTIMIZING DRUG PROPERTIES
LEAD-TO-DRUG DESIGN
Lecture
5th
Dr. Samer Housheh
OPTIMIZING PHARMACOKINETICS
Aims
• To improve pharmacokinetic properties of lead compound
• To optimize chemical and metabolic stability (stomach acids / digestive enzymes / metabolic
enzymes)
• To optimize hydrophilic / hydrophobic balance (solubility in blood / solubility in GIT / solubility
through cell membranes / access to CNS / excretion rate)
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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 membrane - to avoid rapid excretion
• Drugs must have both hydrophilic and lipophilic characteristics
• Many drugs are weak bases with pKa’s 6-8
SOLUBILITY AND MEMBRANE
PERMEABILITY
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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
‘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)
Methods:
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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
Disadvantage:
• May introduce unwanted side effects
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VARY PKA
Rationale:
• Varying pKa alters percentage of drug which is ionized
• Alter pKa to obtain required ratio of ionized to unionized drug
Method:
• Vary alkyl substituents on amine nitrogens
• Vary aryl substituents to influence aromatic amines or aromatic carboxylic
acids
Disadvantage:
• May affect binding interactions
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METABOLIC DRUG STABILITY
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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 (Delays) attack by nucleophiles or enzymes
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‘ELECTRONIC SHIELDING’ OF NH2
Rationale:
• Used to stabilize 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
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STEREOELECTRONIC EFFECTS
• Steric and electronic effects used in combination
• Increases chemical and metabolic stability
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BIO-ISOSTERES
• Replace susceptible group with a different group without affecting activity
• Bio-isostere shows improved pharmacokinetic properties
• Bio-isosteres are not necessarily isosteres
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METABOLIC BLOCKERS
• Metabolism of drugs usually occur at specific sites. Introduce groups at a
susceptible site to block the reaction
• Increases metabolic stability and drug lifetime
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REMOVE / REPLACE SUSCEPTIBLE
METABOLIC 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)]
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INTRODUCING SUSCEPTIBLE
METABOLIC GROUPS
• 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
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MINIMIZING TOXICITY
• Stabilize compounds against metabolic activation
✓produce various isosteres
✓metabolic blocking/steric hinderance
✓modulation of compound electronics
• Introduction of an alternative metabolic site
• Alteration of the SAR at the activating enzyme
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OPTIMIZATION OF METABOLIC PROPERTIES IN
DRUG (LEAD) DEVELOPMENT
REDUCING DRUG TOXICITY
Example - varying substituents
• Fluconazole (Diflucan) - antifungal agent
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PRODRUGS
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PRODRUGS
Definition:
• Inactive compounds which are converted to active compounds in the body.
Uses:
• Improving membrane permeability
• Prolonging activity
• Masking toxicity and side effects
• Varying water solubility
• Drug targeting
• Improving chemical stability
ALKYL ESTERS
Alkyl esters enhance lipophilicity
• Readily cleaved by esterases in blood, liver and other tissues
• Simple alkyl esters are more slowly cleaved
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• Phosphate ester enhance water solubility
✓ Cleaved by phosphonate esterases
✓ After cleavage drug may be very lipophilic and precipitate
• Carbonates and carbamates are often enzymatically more stable than simple esters
• Amides are only used to a smaller extend because they bioconversion using peptidases
is not rapid enough
• Oximes are prodrugs of ketones, amidines and guanidines.
✓Converted by P450 enzymes
✓Makes drug more lipophilic
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PRODRUGS TO LOWER WATER
SOLUBILITY
• Used to reduce solubility of foul tasting orally active drugs
• Less soluble on tongue
• Less revolting taste
• Improves membrane permeability
• Many nucleoside drugs are not able to cross membranes
• mask polar and ionizable groups
PRODRUGS TO IMPROVE
MEMBRANE PERMEABILITY
Esters
• Used to mask polar and ionizable carboxylic acids
• Hydrolyzed in blood by esterases
• Used when a carboxylic acid is required for target binding
• Leaving group (alcohol) should ideally be non-toxic
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N-METHYLATION OF AMINES
• Used to reduce polarity of amines
• Demethylated in liver
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MUCHAS GRACIAS
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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)
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PRODRUGS TO IMPROVE
MEMBRANE PERMEABILITY
Trojan Horse Strategy
• Prodrug designed to mimic biosynthetic building block
• Transported across cell membranes by carrier proteins
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OTHER PRODRUG MECHANISMS
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PRODRUGS TO INCREASE
CHEMICAL STABILITY
Example:
• Hetacillin for ampicillin
• Ampicillin is chemically unstable in solution due to the α-NH2 group attacking
the β-lactase ring
• ‘N’ in heteracillin is locked up within a heterocyclic ring
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PRODRUGS USED TO TARGET
DRUGS
Example:
• Hexamine
✓ Stable and inactive at pH>5
✓ Stable at blood pH
✓ Used for urinary infections where pH<5
✓ Degrades at pH<5 to form formaldehyde (antibacterial agent)
PRODRUGS TO PROLONG ACTIVITY
Mask polar groups
• Reduces rate of excretion
Example:
• Azathioprine for 6-mercaptopurine
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Example:
Valium for nordazepam
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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
• Mask groups responsible for toxicity/side effects
• Used when groups are important for activity
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CAPECITABINE REQUIRES
MULTIPLE STEPS FOR ACTIVATION
• Human carboxylesterases 1 and 2 in the liver cleave the ester bond of
the carbamate
• It is followed by fast spontaneous decarboxylation
• Cytidine deaminase in the liver and in tumor convert the amine into a
carbonyl moiety
• Finally tymidine phosphorylase liberates the active drug fluoruracil
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PROBLEMS IN THE USAGE OF
PEPTIDES/PROTEINS AS DRUGS
• Instability of proteins/peptides in the gastrointestinal tract due to
proteolysis
• Low permeability across membranes due to the high molecular mass
and the high polar surface
• Inefficient to pass the blood-brain barrier
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APPROACHES TO IMPROVE
PHARMACOKINETICS OF PROTEINS
• Co-administration of protease inhibitors
• Encapsulation, coatings or other delivery methods (Liposomes)
• Cell-membrane permeabilization:Addition of fatty acids, bile salts surfactants and Aspirin
• Modifications of tight junctions: Co-addition of certain toxins or polymeric materials (dangerous, because that may
allow passage of potential harmful compounds from the gut into systemic circulation)
• Receptor-mediated endocytosis:Vitamin B12 receptor, Fc receptor (no size limit)
• Usage of membrane-transporters: Covalent link recognizing epitope for bile acid transporter, di- and tripeptide
transporter, glucose transporter (small cargos)
• Increase of drug lipophilicity: Addition of functional groups by conjugating labile lipid attachments (e.g. to Lys
sidechains, Insulin)
PROTEIN MODIFICATION
Insulin:
• Developed a form that is monomeric and can more easily get into the
systemic circulation after subcutaneous injection. This was achieved by
various mutations that stabilized the monomeric form (insulin lispro (Eli
Lilly); Novorapid, (NovoNordisk))
• Other examples: human interleukin-2 (IL-2) was converted into the
desglycosylated form (Proleukin, Chiron, a des-alanyl interleukin).
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MUCHAS GRACIAS
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