MedChem5 Lead PDF

Approaches of
Classical Medicinal Chemistry
Optimizing Drug Properties

Lead-to-Drug Design
• •
Mittwoch, 30. September 2009

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)

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
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:

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 Systemic antifungal agent

solubility - skin infections only improved blood solubility
Disadvantage:
• May introduce unwanted side effects

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
Antithrombotic Decreased basicity

but too basic N locked into heterocycle

Metabolic 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 Terminal amide

D1927
Steric
Shield
Blocks hydrolysis of terminal amide

‘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

Stereoelectronic Effects
• 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)

Bio-Isosteres
• Replace susceptible group with a different group without affecting activity

• Bio-isostere shows improved pharmacokinetic properties
• Bio-isosteres are not necessarily isosteres
Pyrrole ring =
bioisostere for amide

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
Oral contraceptive
- limited lifetime

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)]
Unsusceptible
Susceptible group
group
TOLBUTAMIDE
Rapidly excreted - short lifetime

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
Anti-arthritic agents

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
D.C. Evans, T.A. Baille, Curr. Oppin. Drug Disc. Develop. 8 (2005), 44-50

H O
CP-85958 (Pfizer)
S
O
Liver-toxic in monkeys
OH N
HO O O HO
S S
O O
OH N OH N
F F
metabolized to the ring-opening to produce

corresponding lactol a very reactive, alkylating aldehyde

Optimization of metabolic properties
in drug (lead) development
CP-85958 (Pfizer)
H O
HO 2 C O
S
Liver-toxic in monkeys
OH N
O O
F
S
NH
O F
F
O
O O
F
S
S
N O S
H O
F
F OH N
F O OH N
H 3C F
F
F
Metabolic stabilization Increase metabolic lability

block lactol formation at other site
replacement of the carboxylic acid major route: metabolic O-demethylation

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

Example - varying substituent position
• Dopamine antagonists
Inhibits P450 enzymes

No inhibition of P450 enzymes

Immunogenicity
• antigen: any substance that can be specifically
bound by B-cell or T-cell receptors
• immunogenicity: ability of substances or invoke a

humoral or cell-mediated immune response. Depends
on the degree of “foreignness” or “non-
selfness” (related on evolutionary distance)
• large-size molecules are better immunogens

(larger interaction interface, more potentially
immunogenic sites), also heterogeneity increases
immunogenicity
• epitopes: parts of the molecule that bind to B-cell

or T-cell receptor (antigenic determinants)
Surface residues were mutated in an allergen such

significant reduction of the binding to human serum
IgE occurred. Such a mutated allergen can than be
used as a vaccine to produce antibodies against the wt-
• • allergen.
wild type mutants Holm, J. Immunol. 173 (2004), 5258

B-cell mediated immune response
• B-cell triggered immune reaction involves binding of antigens to antibodies, that

are anchored on B-cells
• it recognizes accessible epitopes of peptides and proteins
• B-cell epitopes can be sequential or non-sequential, but from denatured protein

only
• sequential epitopes will• recognized

T-cell mediated immune response
• T-cell triggered immune reaction involves

formation of antigen, T-cell receptor and
MHC (major histocompatibility complex)
• it presents fragments from proteins and
peptides processed by the cell (no need to
be surface exposed)
• The APC-T-cell complex then triggers the

immune response (production of cytokines,
cell-lysing factors etc.)
• •

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 enhance lipophilicity
•readily cleaved by esterases in blood,
liver and other tissues
•simple alkyl esters are more slowly
Ethers
OR
Carbonates
R1 O
O
O
OR –SH O O R2 cleaved
R1 O
S O R2
O
Esters
O • phosphate ester enhance water solubility
•cleaved by phosphonate esterases
–COOH S R OR –OH
O R1 O Phosphates
•after cleavage drug may be very lipophilic

O O R2 O
O P OH
Amides
O
–PO(OH)2 OH
O
and precipitate
NHR O O P OH
OH
Carbamates
O
–NH N O
O
P OH
•carbonates and carbamates are often
enzymatically more stable than simples esters
H
O NR OH
N-Mannich bases Oximes Imines
N N
O
R2
N
OR
N
R
• amides are only used to a smaller extend
H
R1 because they bioconversion using peptidases is
not rapid enough
–C O
• oximes are prodrugs of ketones, amidines

and guanidines.
•converted by P450 enzymes
•makes drug more lipophilic
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
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

Example:
Palmitate ester of chloramphenicol (antibiotic)
Palmitate ester
Esterase
Chloramphenicol

Prodrugs for improved lipophilicity or permeability
Prodrug name Functional group Structure Prodrug strategy
(therapeutic area)
Enalapril (angiotensin- Monoethyl ester of O O t Bioconversion by esterases
converting enzyme enalaprilat t The oral bioavailability of enalaprilat in
inhibitor) N humans is 36–44%
N t 53–74% of the administered dose is
H
O COOH absorbed3,172
Pivampicillin Pivaloylmethyl ester of O t Bioconversion by esterases

(`-lactam antibiotic) ampicillin O t The oral bioavailability of 32–55% for
O
H2N HN N ampicillin increased to 87–94% for
O pivampicillin173,174
O
O S
Oseltamivir Ethyl ester of t Bioconversion by esterases

O
(anti-influenza) oseltamivir t The oral bioavailability of less than 5% in rat
carboxylate O O and marmoset for oseltamivir carboxylate
O increased to 80% for oseltamivir in
N humans80–82
H
NH2
Adefovir dipivoxil Bis-(pivaloyloxy- NH2 t Bioconversion by esterases and

(antiviral) methyl) ester of phosphodiesterases
adefovir N t The oral bioavailability of ~10% for adefovir
N
O
increased to 30–45% for adefovir dipivoxil78,79
N N O
O P O O
O O

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

Prodrugs for improved aqueous solubility
(therapeutic area)
Sulindac Oxide prodrug of F COOH t Bioprecursor prodrug that is reduced to the
(non-steroidal anti- sulindac sulphide active sulphide form after oral absorption
inflammatory) CH 3
t ~ 100-fold increase in aqueous solubility62,65
O
S
CH 3
Miproxifene Phosphate ester of t Bioconversion by alkaline phosphatases

phosphate, TAT-59 miproxifene/DP-TAT-59 N t Aqueous solubility at pH 7.4 increased by
O
(anticancer) ~1,000-fold69
t Enhanced bioavailability to 28.8% in rats and
23.8% in the dog66
t Dose-linear pharmacokinetics in humans69
O
HO P O
OH
Fosamprenavir Phosphate ester of Ca2+ t Bioconversion by alkaline phosphatases

O
(antiviral) amprenavir -
t 10-fold increased aqueous solubility
O P O-
t More simplified and patient compliant
O
H dosage regimen
O O N N NH2
S t Prolonged exclusive patent70–72
O O O

(Mis)using carrier to help crossing membranes
Blood
Blood–brain
barrier Brain
LATs
OATs Multiple drug carriers in different tissues,
OCTNs all of which may need to be permeated:
OATPs
MRPs BcrP, breast cancer-resistant protein (also
Intestine MCT1
MDRs known as ABcG2); LAts, l-type amino-acid
OATPs transporters;
Liver
MCTs Mct1, monocarboxylate transporter 1 (also
PETP1
OCTs NTCP known as sLc16A1);
MDR
MRPs MDr, multidrug-resistant;
OATPs
MRPs MDR MrPs, multidrug-resistance-related proteins;
OATs
SPGP NPt1, sodium phosphate transporter 1 (also
NPTs known as sLc17A1),
BCRP
D OCTs NtcP, sodium-dependent taurocholate co-
MRPs
OCTNs transporter (also known as sLc10A1);
Other: skin, lung,
retina, nasal passage MRPs OAts, ornithine aminotransferases;
OAtPs, organic anion transporting
Various Kidney polypeptides;
Octs/OctNs, organic cation transporters;
PEPTs
PetP1, peptide transporter 1 (also known as
OATPs
sLc15A1);
OATs
NPT1 sPGP, sister P-glycoprotein (also known as
URAT1 ABcB11);
OCTs UrAt1, urate anion exchanger 1 (also known as
OCTNs
MDRs
sLc22A12)
Dobson et al, Nat. Rev. Drug Discov. 7 (2008), 205.

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

Prodrugs to exploit carrier-mediated absorption
Prodrug name Functional Structure Prodrug strategy
(therapeutic area) group
Valacyclovir -Valyl ester O t Bioconversion by valacyclovir
(antiviral) of acyclovir N hydrolase (valacyclovirase)
HN t Transported predominantly
N NH3+ Cl– by hPEPT1
H2N N
t Oral bioavailability improved
O
O from 12–20% (acyclovir) to 54%
O (valacyclovir)90–92,182
Valganciclovir -Valyl ester O t Bioconversion by intestinal

(antiviral) of ganciclovir N and hepatic esterases
HN t Transported predominantly
N NH3+ Cl– by hPEPT1
H2N N
O
from 6% (ganciclovir) to 61%
O (valganciclovir)183,184
HO
Midodrine Glycyl amide of O t Bioconversion by unknown

(vasopressor) desglymidodrine peptidase
O t Transported by hPEPT1
NH3+ Cl–
N from 50% (desglymidodrine)
H
O OH to 93% (midodrine)94
XP13512 Isobutanoyloxy- O O t Bioconversion by esterases

(restless leg ethoxy HO t Transported by both MCT1
syndrome, carbamate of N O O and SMVT
H
neuropathic pain) gabapentin O t Oral bioavailability improved
from 25% (gabapentin) to 84%
(XP13512) in monkeys98,99
hPEPT1, human peptide transporter 1 (also known as SLC15A1); MCT1, monocarboxylic acid transporter 1 (also known as SLC16A1);
SMVT, sodium-dependent vitamin transporter (also known as SLC5A6).

Other prodrug mechanisms
Prodrugs for other purposes
(therapeutic
area)
Levodopa Carboxylic acid of OH t Crosses the blood–brain
(Parkinson’s dopamine H2N barrier and enters the brain
disease) O by using LAT1
HO t Is decarboxylated
to dopamine by
HO
aromatic amino-acid
decarboxylase136,137
Pradefovir 2-(3-chlorophenyl)-[1,3,2]di NH2 t Undergoes cytochrome
mesylate oxaphosphinane of adefovir N
P450-catalyzed oxidation to
(antiviral) N adefovir predominantly in
N O the liver154,155,187
N O
O P
O
Cl
Simvastatin, R= Inactive lactone forms HO O t Bioprecursor prodrugs that

CH 3; lovastatin, are converted into the active
R=H (hypercho- O hydroxyl acid forms in the
O
lesterolaemia) H liver156,157,188
O
H
R
Bambuterol Bisdimethylcarbamate of CH3 CH3 t Prolongs duration of drug

(asthma) terbutaline action
N O O N
H3 C CH3 t Undergoes cascade of
O O
hydrolysis and oxidation
reactions to terbutaline163,165
H
N
HO C(CH3)3
LAT1, type 1 -type amino-acid transporter.

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

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
6-Mercaptopurine Azathioprine
(suppresses immune response) • Slow conversion to 6-mercaptopurine
• Short lifetime - eliminated too quickly • Longer lifetime

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

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 Aspirin

• Analgesic, but causes stomach • Phenol masked by ester
ulcers due to phenol group • Hydrolyzed in body

Capecitabine requires multiple steps for activation
O O
HN O HN OH NH2 O
F F F F
N N N HN O
CES1, CES2 CDA dThdPase
–CO 2 F
O N (liver) O N (liver, tumours) O N (tumours) HN
O N
H3C O H3C O H3C O H3C O
O N
H
HO OH HO OH HO OH HO OH
Capecitabine 5v-dFCyd 5v-dFUrd 5v-Fluorouracil
•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

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
Potentially immunogenic protein modifications
Modification Effect
Engineered modifications
Amino-acid sequence Human versus analogues and non-human proteins
Chemical modification Acylation, PEGylation
Pharmaceutical formulation Lyophilization, micro-encapuslation
Unwanted modifications during processing, production and storage
Chemical degradation Deamidation, oxidation
Physical degradation Denaturation, aggregation, fibrillation, misfolding
PEG, polyethylene glycol.
• •

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))
Hexamer Dimer Monomer
Biological membrane
• other examples: human interleukin-2 (IL-2) was converted into the

desglycosylated form (Proleukin, Chiron, a des-alanyl interleukin).
• •

Preventing protein misfolding during storage
• Protein misfolding is influenced by shear/shaking , temperature, pH and
protein concentration to a large extend
• Irreversible aggregation by disulfide-shuffling, stable hydrophobic
association
• Fibrillation may cause toxicity of proteins that are otherwise not harmful
• Often a few “gatekeeper” residues are involved in forming aggregates and
removing these can tip the balance towards a stable monomeric form
• small molecules that can from hydrogen bonds with beta-strands can
prevent fibrillation
• addition of sugars or salts that tend to be excluded from protein
surfaces and hence favor compacts states
• amino acids such as Arg or Glu (50mM) that neutralize opposite charges
• polyols, PEGs and other polymers that sterically hinder protein-protein
interactions
• addition of detergents and other amphiphiles to reduce the effects from
shear
• addition of cyclodextrins to remove aggregation (used for insulin, growth
hormones (these bind to unfolded states, in particular to aromatic residues
preventing their aggregation) (caution: some cyclodextrins may extract
•membrane components) •
• sometimes lyophilization can reduce problems due to long-term storage
Modifications of peptides to increase
plasma lifetimes and BBB passage
D-amino acids
endgroup
modification
Amid-bond surrogate
cyclization Peptoid
N-alkylation
Aza peptide
•modification of backbone: Esters, Ketones

•Increase BBB passage into the CNS:
Reduce size of molecule (< 500), coupling to a lipid carrier such as triglyceride or a liposome, increase
of lipophilicity (acylation, methylation etc.)
conversion into prodrug adding a lipid with a brain-specific lipase cleavage site
usage of endogenous transport mechanism (requires certain sequence modifications, e.g. introduction
• •
of cationic charges or modification with polyamines, glycosylation to facilitate transport with glucose
transporters, coupling to cell-penetrating peptides (penetratins)

Other Protein Modifications
• Acetylation
– Attachment of acetyl groups or fatty acid groups to surface residues
can increase the affinity to serum albumin so that degradation is
retarded and circulation time is increased
– more efficient for small proteins
– examples: insulin, glucagon-like peptide 1, interferon-α, desmopressin
• PEGylation
– reduces plasma clearance by reducing the metabolic rate and receptor-

mediated uptake from system circulation by increasing the size
(reduced renal clearance)
– shields antigenic and immunogenic epitopes and thereby reduces
immunogenic reactions
– unfortunately, product heterogeneity is large (difficult product quality

• control, difficult approval).
•

PEGylation
O PEG O O O
O
N N PEG X (CH2)m O N N
PEG O N
Cl N O PEG
O
m=2X=0
Linear PEG-OH H (OCH2CH2)n OH
m=3X=0
m = 2 X = NH
Linear m–PEG-OH CH3 (OCH2CH2)n OH

Cl
O
O
N N
Branched m–PEG2 m–PEG O C N O PEG OH PEG O O NO2
H Cl N O PEG
m–PEG O C N (CH2)4 OH
H O
different types of PEG O O O O O Cl
PEG O CH2 O N PEG O O N PEG O O Cl
O O Cl
activation reagents for pegylation
•proteins are pegylated to reactive side-chains, e.g. the free N-terminus or the ε amino
group of lysines. Possibly also with thiol groups of Cys residues
•the PEG part is highly solvated and largely increases the solubility of the complex
•polymer nanoparticles have been demonstrated to pass the blood-brain barrier
•targets:
• •
proteins,peptides, small-molecule drugs, antibodies, ab-fragments

Pharmacokinetics of PEGylated drugs
Plasma levels of interferon after subcutaneous injection
interferon α2a 40kDa-PEG-IFN-α2a
O
O
N
•Special linker allow controlled release

O O O
O
m–PEG S
O N S
H of the drug from the PEG attachment,
R-NH2 e.g. when using the p- or -o-disulfide of
benzyl urethan.
O
O O NH-R
m–PEG S Inside the endosomal compartment of a

O N S
H
cell the mildly reducing conditions
Reduction
Rv-SH release the cargo
O
•m–PEG O N
S
S-Rv
•
CO2
R-NH2
H S

Commercial pegylated drugs
Modified proteins and protein-delivery systems approved for marketing

Product (company) Drug Modification/delivery system Administration route
Proleukin (Chiron) Aldesleukin Analogue Intravenous
Humalog (Eli Lilly) Insulin lispro Analogue Subcutaneous
NovoRapid (Novo Nordisk) Insulin aspart Analogue Subcutaneous
Neulasta (Amgen) PEGinterferon _-2a Mono-pegylated Subcutaneous
Pegasys (Roche) Pegfilgrastim Mono-pegylated Subcutaneous
Somavert (Pharmacia) Pegvisomat Multi (4–6)-pegylated Subcutaneous
Levemir (Novo Nordisk) Insulin detemir Mono-acylated Subcutaneous
Nutropin Depot (Genentech) Human growth hormone PLGA microspheres Subcutaneous
InductOs (Wyeth (MDT)) Bone morphogenic protein 2 Absorbable collagen sponge Implanatable medical device
PLGA, poly(lactide-co-glycolic acid)
• •

DDS Systems on the commercial market
• •

Lipid-Assisted Delivery
Lipids can solubilize drugs in

the intestinal compartment
by incorporating them into
micelles, mixed micelles or
vesicles
Lipids can altering the

pathway portal vein vs.
lymphatic system and hence
may thereby reduce first
pass metabolism in the liver
Lipids can interfere with the enterocyte-

based transport and the involved metabolic
processes,
• potentially changing
• drug uptake,
efflux or formation of metabolites

Liposome as (smart) delivery systems
• Liposomes are spherical aggregates of lipids, that can accommodate
hydrophilic drugs in the aqueous compartment and hydrophobic drugs in the
b liposomal membrane
a • Liposomes are biocompatible
• Liposome-incorporated pharmaceuticals are protected from the inactivating
effect of external conditions,yet do not cause undesirable side reactions.
•Liposomes provide a unique opportunity to deliver pharmaceuticals into cells
or even inside individual cellular compartments. j
i
q
k
h
d
s
c g
p r
+ l
+
+
–
o n m
Liposome with protective polymer (i) or targeting ligands

such as antibody (j), a diagnostic label (k), positively
charged lipids (l) allowing for the complexation with
DNA (m), stimuli-sensitive lipids (n) or polymers (o), cell-
liposomes with surface- penetrating peptides (p), viral components (q). In
antibody-target addition to a drug, liposome can loaded with magnetic
• grafted
• PEG for protection
immunoliposomes particles (r) for magnetic targeting or with colloidal gold
and antibody for targeting
or silver particles (s) for electron microscopy.

Drug Targeting
Linking a biosynthetic building block
• 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
Non selective alkylating agent

Toxic Uracil Mustard
• 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

Linking drugs to monoclonal antibodies
Example:
Anticancer agents
Rationale:
• 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

Antibodies
Fab
Fv
VH
•Antibodies can mostly be described by the

immunoglobulin fold. Antibodies are
heterotetramers consisting of two heavy and
two light chains. The antibodies are heavily
glycosylated. The antigen-binding molecule can
be reduced to the Fv fragment consisting of the
VL and VH units. Those can be covalently linked
to form a single-chain mini-antibody scFv.
•Complete
• antibodies have long serum
• half-lives. Fab and scFv fragments that lack the Fc
region have short serum half-lives. This can be improved by pegylation, that also reduces
immunogenicity.
Antibody Structure
VH/VL CH1/CL CH1/CL VH/VL
CH2
CH3
•antibodies
•
are made of a heavy chain and a light chain, that are linked together by a
•
disulfide bond. The antigen recognizing element is located in the complementary-
determining regions (CDRs) of the VH elements
Avoiding Immune Response:
Humanizing Antibodies
Mouse hybridoma In vitro antibody libraries
Transgenic mouse
Human hybridomas
Mouse Chimeric Humanized Human
Genetic engineering
V gene cloning
CDR grafting
Eukaryotic expression
•Antibodies produced in mouse are potentially highly immunogenic in human

• In order to reduce immunicity chimeric antibodies have been developed
constructed by taking taken human constant and mouse variable regions
• Immunicity could be further reduced by grafting mouse CDRs onto human
antibodies
• •

Avoiding Immune Response:
Using in-vitro and in-vivo human ab techniques
•synthetic human
antibody libraries can
be constructed, in
which the CDR loops are
varied, and binders can
be selected from those.
•Alternatively,
transgenic mice can be
used, in which the
human gene for
antibody production is
contained, producing
human antibodies in
mice.
• •

Selecting Binders by Phage Display
Amplification
in E.coli
Immobilized
antigen
Binding selection Washing
• Binders can be selected by phage display or ribosome display

techniques.
• In phage display phages are used, in which antibodies are displayed
on the surface of the phages, while the inside of the phage contains a Nonbinding phage
plasmid encoding for the antibody DNA.
• Large libraries can be produced and screened for binder (e.g. by
affinity chromatography) and amplified in E.Coli and used for further
selections for improved binders.
• •
• Good binders can finally be isolated as individual clones and
sequenced.
Targets of Antibodies
Targ e t Ag e nt
Vascular endothelial growth factor Bevacizumab
Lymphocyte function-associated antigen 1 Efalizumab
Epidermal growth factor receptor C etuximab
Human epidermal growth factor receptor 2 Trastuzumab
Immunoglobulin E (IgE) O malizumab
C D-3 Muromonab-C D3
C D-20 Rituximab, ibritumomab tiuxetan,
131
I-tositumomab
C D-33 G emtuzumab
C D-52 Alemtuzumab
F protein of RSV subtypes A and B Palivizumab
C D-25 Basiliximab, daclizumab
Tumour-necrosis factor-_ Adalimumab, infliximab
G lycoprotein IIb/IIIa receptor Abciximab
_4-Integrin subunit Natalizumab

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Approaches of

Classical Medicinal Chemistry

Optimizing Drug Properties

Mittwoch, 30. September 2009

• To improve pharmacokinetic properties of lead compound

• To optimize chemical and metabolic stability (stomach acids /

• To optimize hydrophilic / hydrophobic balance

Mittwoch, 30. September 2009

• Drugs must be polar - to be soluble in aqueous conditions- to

• Drugs must be ‘fatty’ - to cross cell membrane - to avoid rapid

• Drugs must have both hydrophilic and lipophilic characteristics

• Many drugs are weak bases with pKa’s 6-8

Mittwoch, 30. September 2009

Mittwoch, 30. September 2009

Mittwoch, 30. September 2009

Antifungal agent with poor Systemic antifungal agent

Mittwoch, 30. September 2009

Antithrombotic Decreased basicity

Mittwoch, 30. September 2009

Antirheumatic agent Terminal amide

Blocks hydrolysis of terminal amide

Mittwoch, 30. September 2009

Mittwoch, 30. September 2009

• Steric and electronic effects used in combination

Mittwoch, 30. September 2009

• Replace susceptible group with a different group without affecting activity

Mittwoch, 30. September 2009

Mittwoch, 30. September 2009

• Metabolism of drugs usually occurs at specific groups.

Rapidly excreted - short lifetime

Mittwoch, 30. September 2009

• Used to decrease metabolic stability and drug lifetime

Mittwoch, 30. September 2009

• stabilize compounds against metabolic activation

Mittwoch, 30. September 2009

metabolized to the ring-opening to produce

Mittwoch, 30. September 2009

Metabolic stabilization Increase metabolic lability

Mittwoch, 30. September 2009

Example - varying substituents

• Fluconazole (Diflucan) - antifungal agent

Mittwoch, 30. September 2009

Inhibits P450 enzymes

Mittwoch, 30. September 2009

• immunogenicity: ability of substances or invoke a

• large-size molecules are better immunogens

• epitopes: parts of the molecule that bind to B-cell

Surface residues were mutated in an allergen such

Mittwoch, 30. September 2009

• B-cell triggered immune reaction involves binding of antigens to antibodies, that

• it recognizes accessible epitopes of peptides and proteins

• B-cell epitopes can be sequential or non-sequential, but from denatured protein

Mittwoch, 30. September 2009

• T-cell triggered immune reaction involves

• The APC-T-cell complex then triggers the

Mittwoch, 30. September 2009

Mittwoch, 30. September 2009

•after cleavage drug may be very lipophilic

N-Mannich bases Oximes Imines