Getting a drug to the target in the body

TEAM 2013

DRUG DESIGN AND DEVELOPMENT 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- optimizing target interactions 8) Drug design - optimizing pharmacokinetic properties 9) Toxicological and safety tests 10) Chemical development and production 11) Patenting and regulatory affairs 12) Clinical trials

Pelepasan(LIBERATION) Pelarutan(DISOLUTION) Difusi (DIFUSION) Transfer Absorbsi

GOOD FARMAKOKINTIK PROFILE

DRUG DESIGN

Aims
To improve pharmacokinetic properties of lead compound To optimize chemical and metabolic stability

To optimize hydrophilic / hydrophobic balance

To optimize solubility To optimize drug half life To optimize distribution characteristics

PHARMACOKINETICS - DRUG DESIGN

Notes
Drugs must be sufficiently polar to be soluble in aqueous conditions Drugs must be sufficiently polar to interact with molecular targets Drugs must be sufficiently fatty to cross cell membranes Drugs must be sufficiently fatty to avoid rapid excretion Drugs must have both hydrophilic and lipophilic characteristics

Many drugs are weak bases with pKas 6-8

A high solubility drug is defined by the BCS as the highest dose that is soluble in 250 mL or less in aqueous media from pH 1 to 7.5. A drug is considered rapidly dissolving if no less than 85% of label claim is released within 30 min across the aforementioned pH range in either USP dissolution apparatus I (baskets) at 100 rpm or USP dissolution apparatus II (paddles) at 50 rpm. A compound is considered highly permeable by the BCS if its extent of absorption in humans is 90% or more of an administered dose. Drugs are then defined based on these solubility, permeability, and dissolution characteristics to fall within one of four BCS classifications.

Solubility and membrane permeability

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

Solubility and membrane permeability

Vary alkyl substituents

Methylene shuffle
CH3 O HN N O CH3 N N
CH3 O HN N O N

Extra bulk
CH3
N N

O HN N N N N

O S N N

CH3

O S N

CH3

Methylene shuffle

H 3C O S N N O

Viagra

N CH3

UK343664

CH3

H 3C

Second-generation anti-impotence agent Increased selectivity Excess lipophilicity

Reduced lipophilicity Better in vivo activity

Solubility and membrane permeability

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
CH3I

Methods

OH

OMe

CH3COCl R NHR R

H N

CH3 O

R C O

OH

H+ / R'OH

R C O

OR'

Solubility and membrane permeability

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
Cl N N H C O Cl S

N N

N OH C

N N F

Cl

Tioconazole
solubility - skin infections only

Fluconazole
Systemic antifungal agent improved blood solubility

Disadvantage of adding polar groups May introduce unwanted side effects

Solubility and membrane permeability

Vary pKa 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

Solubility and membrane permeability

Vary pKa

N O N H N O (I)
N NH2

N O N H N O PRO3112 N

H2N

NH

amidine

Antithrombotic Too basic

Decreased basicity Nitrogen locked into heterocyclic ring

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 Sleeping agents

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 Examples Enalapril for enalaprilate (antihypertensive)

CH3 RO O N H N O CO2H

R=Et Enalapril R=H Enalaprilit

Examples Candoxatril for Candoxatrilat (protease inhibitor)

OMe

Prodrugs to improve membrane permeability

OMe

O HO O O Candoxatrilat H N CO2H
5-indanyl group O

O H N O O Candoxatril CO2H

Notes 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

Prodrugs to improve membrane permeability

N-Methylation of amines Used to reduce polarity of amines Demethylated in liver
O

Examples - Hexobarbitone

Me N NH

O Me

Prodrugs to improve membrane permeability

Trojan Horse Strategy Prodrug designed to mimic biosynthetic building block Transported across cell membranes by carrier proteins Example -Levodopa for dopamine
HO CH2 CH2 HO NH2 HO HO CH2 C NH2 CO2H H

Dopamine Useful in treating Parkinsons Disease Too polar to cross cell membranes and BBB

Levodopa More polar amino acid Carried across cell membranes by carrier proteins for amino acids Decarboxylated in cell to dopamine

Prodrugs to improve membrane permeability

Blood supply Brain cells

H2N

COOH

H2N

COOH

L-Dopa
H2N

Enzyme

Dopamine BLOOD BRAIN BARRIER

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
OH H H N
Cl

Cl Cl

H H N O OH

Cl

Esterase
O2N

O OH

H O2N

Chloramphenicol

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)
HO O

Succinate ester
O O Cl Cl

OH H H N O OH

Cl Cl

H H N O OH

Esterase
O2N

H O2N

Chloramphenicol

Prodrugs to increase water solubility

Example: Phosphate ester of clindamycin (antibacterial)

CH3CH2CH2

Me N

H C Cl H H C CH3

N C H O H HO OH H H SCH3 H OPO32-

Less painful on injection

Prodrugs to increase water solubility

Example: Lysine ester of oestrone
Me H H2N NH2 O Prodrug H H H O
H2N O Lysine

O
H NH2 + OH HO Oestrone H H

Me

Notes: Lysine ester of oestrone is better absorbed orally than oestrone Increased water solubility prevents formation of fat globules in gut Better interaction with the gut wall Hydrolysis in blood releases oestrone and a non toxic amino acid

Jurnal international

Mode of action of penetration enhancers in human skin

Chemical enhancement of percutaneous absorption in relation to stratum corneum structural alterations

A lamellar matrix model for stratum corneum intercellular lipids III. Effects of terpene penetration enhancers on the release of 5-fluorouracil and oestradiol from the matrix
The routes of penetration of ions and 5-fluorouracil across human skin and the mechanisms of action of terpene skin penetration enhancers Predicting Oral Absorption and Bioavailability

dodecyl-2-N,N-dimethylamino propionate hydrochloride (DDAIP.HCl)

Fig. 1b: Mechanism of enhanced permeation. Real-time confocal microscopy of the DDAPI on uptake of Green Nucleic Acid Stain compared with control

FIGURE 1 | Human skin structure and effect of delivery systems and permeation enhancers on

permeation of drug molecules. Three-dimensional(3D) structure of human skin (left column): first-generation approach to transdermal delivery is limited primarily by the barrier posed by skins outermost layer called the stratum corneum, which is 1020 m thick. Underneath this layer is the viable epidermis, which measures 50100 m and is avascular. Deeper still is the dermis, which is 12 mm thick, and contains a rich capillary bed for systemic drug absorption and nerve endings just below the dermalepidermal junction. Chemical permeation enhancers and drug delivery systems interact with the intercellular lipids in the stratum corneum. This interaction modifies the structural order of the lipids which are originally arranged in multiple bilayer stacks (left column) (electronmicrograph and bilayer model: Reprinted with permission from Ref 16. Copyright 2006 Elsevier). This modification, fluidization, disorder, or rearrangement of the lipids can be monitored by small-angle X-ray scattering (SAXS)/wide-angle X-ray scattering (WAXS) (middle column). Conventional permeation enhancers such as ethanol, oleic acid, propylene glycol and a marketed enhancer, Transcutol, cause disordering of the lipids, but do not disrupt the bilayer configuration (right column). Among the lipid-based delivery systems, liposomes and a submicron emulsion also have a disordering effect, whereas biphasic vesicles appear to cause rearrangement of the organization of the stratum corneum lipids into a Pn3m cubic phase configuration (SAXS pattern: middle column, model: right column). This cubic phase could be an intercellular permeation nano pathway that may explain the increased delivery of interferon (IFN-) by biphasic vesicles.17

MENINGKATKAN SOLUBILITY
penyesuaian pH lingkungan penambahan pelarut yang terlarut dalam air (etanol, gliserin, propilenglikol dll) pemberian surfaktan pembentukan senyawa kompleks (penambahan ligan) pembentukan senyawa garam esterifikasi pembentukan senyawa inklusi (mikro / nanoenkapsulasi)

MENINGKATKAN PERMEABLITAS

meningkatkan kelarutan mengatur waktu retensi dalam saluran cerna menstimulasi lymphatic transport mengubah permeabilitas saluran cerna (surfaktan, makanan berlemak) pengurangan aktivitas efflux membran

saluran cerna

Matur Nuwun

Prodrugs used to target drugs

Example: Hexamine

N N N N
Notes: 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 increase chemical stability

Example: Hetacillin for ampicillin
Ph O
Ph O

Ampicillin
HN N CH3 O OH S N CH3 CH3
O O N H2N HN S CH3 CH3

'Locked' Nitrogen

H3C

Hetacillin

H3C

CH3

OH O

Notes: Ampicillin is chemically unstable in solution due to the a-NH2 group attacking the b-lactam ring Nitrogen atom in heteracillin is locked up within a heterocyclic ring

Prodrugs activated by external influences -sleeping agents

Example: Photodynamic therapy - Foscan
HO

OH NH N

HO

H H H H

HN

OH Notes: Inactive and accumulates in cells Activated by light - method of targeting tumour cells Foscan is excited and reacts with oxygen to produce toxic singlet oxygen Cell destruction is caused by singlet oxygen

Drug Alliances - Synergism Definition:

Drugs which have a beneficial effect on the activity or pharmacokinetic properties of another drug

Sentry Drugs
Definition: A drug that is added to protect another drug Example: Carbidopa
L-DOPA ENZYME
INHIBITION
HO C Me HO CO2H NHNH2

DOPAMINE

CARBIDOPA

Notes 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

Localizing drugs to a target area

Example:Adrenaline and procaine (local anaesthetic) Adrenaline constricts blood vessels at the injection area Procaine is localized at the injection area

Increasing absorption
Example: Metoclopramide
O H N OCH3 Cl NH2 N(Et)2

Notes Administered with analgesics in the treatment of migraine Increases gastric motility and causes faster absorption of analgesics Leads to faster pain relief

Drug stability
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

O C H3C O R H2N

O C O R

ISOSTERE
O C H3C O R CH3 O C NH R

ISOSTERE

Drug stability
Electronic shielding of NH2

O R N H C R'

O R N H C R'

Drug stability
Stereoelectronic Effects Rationale Steric and electronic effects used in combination Increases chemical and metabolic stability
CH3 N H CH3

O H2N C O CH2CH2NEt2

Lidocaine
O C CH2NEt2

Procaine

Local anaesthetic Susceptible to esterases Short duration

ortho Methyl groups act as steric shields Hinder hydrolysis by esterases Amide more stable than ester (electronic effect)

Drug stability
Bio-isosteres Rationale Replace susceptible group with a different group without affecting activity Bio-isostere shows improved pharmacokinetic properties Bio-isosteres are not necessarily isosteres Examples Amides and urethanes for esters (see earlier) Du122290 (dopamine antagonist)
NEt O NH OMe EtSO2
EtSO2 NH NEt

Pyrrole ring = bioisostere for amide

OMe

Sultopride

Du122290

Drug stability
Metabolic blockers Rationale: Metabolism of drugs usually occurs at specific sites. Introduce groups at a susceptible site to block the reaction Increases metabolic stability and drug lifetime

Me C Me Me H O H H

O Me O C O
Me H O H H Me C Me O C O O Me

Megestrol Acetate

6
Me

Metabolism Blocked

Metabolic Oxidation
Oral contraceptive Limited lifetime

Drug stability
Remove / replace susceptible metabolic groups Rationale Remove susceptible group or replace it with a metabolically stable group e.g. modification of tolbutamide (antibiotic)
Susceptible group
Me

O S NH C NH CH2CH2CH2CH3 O O

Unsusceptible group O
Cl S NH C NH CH2CH2CH3 O O

TOLBUTAMIDE

Metabolism
O S NH C NH CH2CH2CH2CH3 O O

Metabolism

HOOC

Rapidly excreted - short lifetime

Drug stability
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 e.g. Salbutamol
Susceptible group
HO HO OH CHCH2 NH C Me Me Me

Unsusceptible group
OH

Shift Group
HO

H C

OH CH2 NH C

Me Me Me

Salbutamol

Catechol O-Methyl Transferase

Catechol O-Me thyl Transferase

Me

MeO OH HO CHCH2 NH C

Me Me

Inactive

Drug stability
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

Examples Anti-arthritic agents

SO2Me Cl N
Cl
CH 2OH

SO2Me

L787257

L791456

CH3
CO 2H

Resistant to metabolism Excessively long half life

Metabolically susceptible

Drug stability
Introducing susceptible metabolic groups Examples Anti-asthmatic agents
O N N N N O N OH Me Me

N NC 4 3 O

O OH Me Me

N O HO
labile

Me N

Me

4 3 O CO2Et
labile

SO2 O UK157147

OH Me Me

Cromakalim

UK143220

Notes Cromakalim produces cardiovascular side effects if it reaches the blood supply Add metabolic instability such that compound is rapidly metabolised in blood UK143220 - ester is quickly hydrolysed by esterases to an inactive acid UK 157147- phenol is quickly conjugated and eliminated

Drug stability
Introducing chemically susceptible groups Rationale Used to decrease drug lifetime Avoids reliance on metabolic enzymes and individual variations Example Atracurium - i.v. neuromuscular blocking agent
MeO O O C O (CH2)5 O OMe

Me
MeO N CH2 CH2

H
CH2 CH2 N OMe

OMe OMe

MeO OMe

Notes 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 surgery

Drug stability
Introducing chemically susceptible groups

Hoffmann Elimination

Me N CH2 CH C H Ph ACTIVE

R O

-H N

Me R H2C CH Ph INACTIVE C O

Drug Targeting
Linking a biosynthetic building block Rationale: Drug smuggled into cell by carrier proteins for natural building block (e.g. amino acids or nucleic acid bases) Increases selectivity of drugs to target cells and reduces toxicity to other cells Example Anticancer drugs
H3C N
HN

Cl
O N

Cl

Cl
O

Cl H N

Non selective alkylating agent Toxic

Uracil Mustard

Notes: Alkylating group is attached to a nucleic acid base Cancer cells grow faster than normal cells and have a greater demand for nucleic acid bases Drug is concentrated in cancer cells - Trojan horse tactic

Drug Targeting
Linking drugs to monoclonal antibodies Rationale Useful for targeting drugs to cancer cells Identify an antigen which is overexpressed on a cancer cell Clone a monoclonal antibody for the antigen Attach a drug or poison (e.g. ricin) to the monoclonal antibody Antibody carries the drug to the cancer cell Drug is released at the cancer cell

Drug Targeting
Targeting gut infections Rationale Design the antibacterial agent to be highly polar or ionised Agent will be too polar to cross the gut wall Agent will be concentrated at the site of infection Example - highly ionised sulfonamides

Drug Targeting
Targeting peripheral regions over CNS Rationale Increase polarity of the drug Drug is less likely to cross the blood brain barrier

Reducing drug toxicity

Rationale Toxicity is often due to specific functional groups

Remove or replace functional groups known to be toxic e.g. aromatic nitro groups aromatic amines bromoarenes hydrazines polyhalogenated groups hydroxylamines
Vary substituents Vary position of substituents

Reducing drug toxicity

Varying substituents Fluconazole (Diflucan) - antifungal agent

N N

N OH C

N N

N N

N OH C

N N

Cl

Cl

UK-47265

Fluconazole
Substituents varied Less toxic

Reducing drug toxicity

Varying substituent position Dopamine antagonists

H N NC N

HN

H N
O

HN

N NC

Inhibits P450 enzymes

No inhibition of P450 enzymes

Drug stability
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

HS N H O

H N

CONHMe

Terminal amide

C O N H3C O CH3 CH3

Steric shield

Blocks hydrolysis of terminal amide

Prodrugs to prolong activity

Mask polar groups Reduces rate of excretion

Example: Azathioprine for 6-mercaptopurine

O2N

SH N
S N Me N

N
N

N H

N
N H N

6-Mercaptopurine

Azathioprine

Suppresses immune response Short lifetime Eliminated too quickly

Slow conversion to 6-mercaptopurine Longer lifetime

Prodrugs to prolong activity

Example: Valium for nordazepam

Me O N

H O N

Cl

N-Demethylation

Cl

Valium

Nordazepam

Prodrugs to prolong activity

Add hydrophobic groups Drug concentrated in fat tissue Slow removal of hydrophobic group Slow release into blood supply Example: cycloguanil pamoate (antimalarial)
CO2 Cl NH3 N N Me OH H3N N Me CO2 CH2 OH

Cycloguanil

Pamoate

Lipophilic

Prodrugs to prolong activity

Add hydrophobic groups Example: Hydrophobic esters of fluphenazine (antipsychotic)
fatty ester
N N O (CH2)8CH3 O H N

CF3

Given by intramuscular injection Concentrated in fatty tissue Slowly released into the blood supply Rapidly hydrolysed in the blood supply

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
O

OH CO2H
H 3C O CO2H

Salicylic acid

Aspirin

Analgesic Causes stomach ulcers Due to phenol group

Phenol masked by ester Hydrolysed by esterases in bloodstream

Prodrugs to mask toxicity and side effects

Example:Cyclophosphoramide for phosphoramide mustard (anticancer agent)

NH P O

Phosphoramidase Cl (liver)

H2N P HO

Cl

Cyclophosphoramide Cl

Phosphoramide mustard

Cl

Non toxic Orally active

Alkylating agent

Prodrugs to mask toxicity and side effects

Example: Antiviral drugs

N HO N N

N
PO Viral NH2 thymidine kinase OH

N N N

N NH2 P P PO

N N N

N NH2

Penciclovir
OH

Cell kinase s

OH

Notes First phosphorylation requires viral thymidine kinase Only activated in virally infected cells Non-toxic to uninfected cells

Prodrugs to mask toxicity and side effects

LDZ for diazepam

Ar

O CH3 N N H O O H NH2

a) Aminopeptidase b) Cyclisation

Ar

N O N CH3

Cl

LDZ
NH2

Cl

Diazepam

Avoids drowsy side effects of diazepam

Prodrugs to mask toxicity and side effects

Mechanism of activation
Ar O CH3 N Cl LDZ NH2 O N H O

H
H
H

NH2 Enz

Ar

CH3 NH2 N

-H

Ar HO

N O N CH3

-lysine

Cl

Cl

H H 2O
+H

H
O N CH3

Ar

N O N CH3
-H

Ar

N O N CH3

Ar

Cl

Cl

Cl Diazepam