the organic chemistry of drug design and drug...
TRANSCRIPT
2009-09-17
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The Organic Chemistry of Drug Design and Drug ActionDrug Design and Drug Action
Chapter 8
Prodrugs and Drug Delivery SystemsProdrugs and Drug Delivery Systems
Prodrugs and Drug Delivery SystemsProdrug - a pharmacologically inactive compound that is converted to an active drug by a metabolic biotransformation
Ideally, conversion occurs as soon as the desired goal for designing the prodrug is achieved.
Prodrugs and soft drugs are opposite:
• a prodrug is inactive - requires metabolism to give active formactive form
• a soft drug is active - uses metabolism to promote excretion
A pro-soft drug would require metabolism to convert it to a soft drug
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Utility of Prodrugs
1. Aqueous Solubility - to increase water solubility so it can be injected in a small volume
2. Absorption and Distribution - to increase lipid solubility to penetrate membranes for better absorption
3. Site Specificity - to target a particular organ or tissue if a high concentration of certain enzymes is at a particular site or append something that directs the drug to a particular site
Utility of Prodrugs (cont’d)4. Instability - to prevent rapid metabolism; avoid first-pass effect
5 P l d R l t tt i l t d 5. Prolonged Release - to attain a slow, steady release of the drug
6. Toxicity - to make less toxic until it reaches the site of action
7. Poor Patient Acceptability - to remove an unpleasant taste or odor; gastric irritation
8. Formulation Problems - to convert a drug that is a gas or volatile liquid into a solid
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Types of ProdrugsDrug Latentiation - rational prodrug design
I. Carrier-linked prodrug
A compound that contains an active drug linked to a carrier group that is removed enzymatically
A. bipartate - comprised of one carrier attached to drug
B. tripartate - carrier connected to a linker that is connected to drug
C. mutual - two, usually synergistic, drugs attached to each other
II. Bioprecursor prodrug
A compound metabolized by molecular modification into a new compound, which is a drug or is metabolized further to a drug - not just simple cleavage of a group from the prodrug
Protecting Group Analogy for the Concept of Prodrugs
Scheme 8.1
A. RCO2H RCO2 Etreaction R'CO2Et R'CO2H
R'CO2H1. O3
R'CH=CH2B. RCH=CH2
EtOHHCl
Δon R
reactionon R 2. H2O2
H3O+
Δ
analogous tocarrier-linked
bioprecursoranalogous to
Keep in mind that a prodrug whose design is based on rat metabolism may not be effective in humans.
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Mechanisms of Prodrug Activation
Carrier-Linked Prodrugs
Most common activation reaction is hydrolysis.
Ideal Drug Carriers
1. Protect the drug until it reaches the site of action
2. Localize the drug at the site of action2. Localize the drug at the site of action
3. Allow for release of drug
4. Minimize host toxicity
5. Are biodegradable, inert, and nonimmunogenicg g
6. Are easily prepared and inexpensive
7. Are stable in the dosage form
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Carrier Linkages for Various Functional Groups
Alcohols, Carboxylic Acids, and Related Groups
Most common prodrug form is an ester
• esterases are ubiquitous
• can prepare esters with any degree of hydrophilicity or li hili itlipophilicity
• ester stability can be controlled by appropriate electronic and steric manipulations
Prodrugs for Alcohol-Containing Drugs
Table 8.1
Ester analogs as
TABLE 8.1. Ester Analogs of Alcohols as Prodrugs
Drug OH Drug OR
Ester analogs as prodrugs can affect lipophilicity or hydrophilicity
X Effect on water solubility
O
C R
O
C CH2NHMe 2
O
C CH2CH2COO -
O
(R= aliphatic or aromatic)
(pKa 8)
(pKa 5)
( K 4)CNH
PO32-
O
C CH2SO3-
(pKa 4)
(pKa 2 and 6)
(pKa 1)
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To accelerate hydrolysis rate:
• attach an electron-withdrawing group if a base hydrolysis mechanism is important
• attach an electron-donating group if an acid hydolysis mechanism is important
To slow down hydrolysis rate:
• make sterically-hindered esters• make sterically-hindered esters• make long-chain fatty acid esters
Another Approach to Accelerate Hydrolysis
Intramolecular hydrolysis of succinate esters
Scheme 8.2
Drug—OH +Drug—O-
Drug—O
-O
O
O
O
O
-OOCCOO-
H OH
Also, acetals or ketals can be made for rapid hydrolysis in the acidic medium of the GI tract.
OO
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Enolic hydroxyl groups can be esterified as well.
S
HOOC
N
OHS
O
O
H N
F
ClN
O
O
F
Cl
S
OO
H2N
oxindole8.1
H2N
8.2antirheumatic agent
Carboxylic Acid-Containing Groups
Esterify as with alcohols
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Maintaining Water Solubility of Carboxylate Prodrugs
C K b i t h i f R d R′
Drug—C—O—CH2CH2—NRR'2+
8.3
O
Can vary pKa by appropriate choice of R and R′
Prodrugs for Phosphate- or Phosphonate-Containing Drugs
P
O
O
OO
2
8.4
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Amine ProdrugsTABLE 8.2 Prodrug Analogs of Amines
Drug NH2 Drug NHX
X
Amides are commonly not used because of stability
O
CR
O
CCHNH3
R
O
COPh CH2NHCAr
OCHAr NAr
y y
Activated amides (low basicity amines or amino acids) are effective
pKa of amines can be lowered by 3 units by conversion to N-Mannich bases (X = CH2NHCOAr)
N-Mannich base (R = CH2NHCOPh) has a log D7.4
two units greater than the parent compound.
phenylpropanolamine hydrochloride (R = H HCl)8 5
NHR
OH
CH3
.8.5
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Another approach to lower pKa of amines and make more lipophilic.
Imine (Schiff base) prodrug
O
NNH2F
OH
hydrolyze imine and id t GABA
progabide8.6
Cl
anticonvulsant
amide to GABA inside brain
A Reductive Carrier-Linked Prodrug Approach
DrugX Z
YNO2
bioreduction
DrugX Z
YNH
OH
:
DrugXH
Z
YN
OH
8.7 8.8
+
Scheme 8.3
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Prodrugs of Sulfonamides
A water soluble prodrug of the anti-inflammatory drug valdecoxib (8 9) has been made (8 10)drug valdecoxib (8.9) has been made (8.10).
S
ONPh
CH3H2NS
ONPh
CH3NNa+
O O
valdecoxib8.9
SO O
parecoxib sodium8.10
O
Prodrug Analogs of Carbonyl Compounds
Drug Drug XTable 8.3
XC
Y
CR
C=OR Y
C=NOHOR'
C
OR'C
NH
OC
NH
SC=NR'
imines oximes ketals
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E l f C i Li k d Examples of Carrier-Linked Bipartate Prodrugs
Prodrug for Increased Water Solubility
Me
HOMe OH
O
OR'
R' = PO3Na2
R' = CCH2CH2CO2 Na
O
Prodrug forms
prednisolone (R = R' = H)methylprednisolone (R = CH3, R' = H)
8 11
O
Me
R
poor water solubility
R = PO3Na2
for aqueous injection or opthalmic use
8.11corticosteroid
Choice of water solubilizing group: The ester must be stable enough in water for a shelf life of > 2 years (13 year half-life), but must be hydrolyzed in vivo with a half-life < 10 minutes.
Therefore, in vivo/in vitro lability ratio about 106.
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To avoid formulation of etoposide with detergent, PEG, and EtOH (used to increase water solubility), it has been converted to the phosphate prodrug.
OOOCH
OO
OO
OOOCH3
HOHO
etoposide (R = H)etoposide phosphate (R = PO3H2)
8.12
ORCH3O OCH3
Prodrug for Improved Absorption Through Skin
CH3
OOR
CH3
O
OCH3
HOCH3
F
F
O3
CH3
corticosteroids - inflammation, allergic, pruritic skin conditions
fluocinolone acetonide (R = H)fluocinonide (R = COCH3)
8.14
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Better absorption into cornea for the treatment of glaucoma
OHRO
dipivefrin (R = Me3CCO)epinephrine (R = H)
8.15
OH
RONHCH3
The cornea has significant esterase activity
Prodrug for Site Specificity
RO
OR
Bowel sterilant
NH
OR
O
oxyphenisatin (R = H)8.16
(administer rectally)
prodrug R = Ac (administer orally)hydrolyzed in intestines
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Prodrug for Site SpecificityThe blood-brain barrier prevents hydrophilic molecules from entering the brain, unless actively transported. The anticonvulsant drug vigabatrin (see Chapter 5) crosses poorly. A glyceryl lipid (8.17, R = linolenoyl) containing one GABA ester and one vigabatrin ester was 300 times more potent in vivo than vigabatrin.
OCOR
8.17
O
O
NH2
ONH2
O
Site Specificity Using Enzymes at the Site of Action
OR
Phosphatase should release the drug selectively in
diethylstilbestrol diphosphate (R = PO3=)
diethylstilbestrol (R = H)8.18
RO
Phosphatase should release the drug selectively in tumor cells. This approach has not been successful because the prodrugs are too polar, enzyme selectivity is not sufficient, or tumor cell perfusion rate is poor.
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Enzyme-Prodrug Therapies
For selective activation of prodrugs in tumor cells
Two steps:Two steps:
1. incorporate a prodrug-activating enzyme into a target tumor cell
2. administer a nontoxic prodrug which is a substrate for the exogenous enzyme incorporated
1. The prodrug-activating enzyme is either nonhuman or a human protein expressed poorly
2. The prodrug-activating enzyme must have high catalytic activity
Criteria for Success with Enzyme-Prodrug Therapies
activity
3. The prodrug must be a good substrate for the incorporated enzyme and not for other endogenous enzymes
4. The prodrug must be able to cross tumor cell membranes
5. The prodrug should have low cytotoxicity and the drug high cytotoxicitycytotoxicity
6. The activated drug should be highly diffusable to kill neighboring nonexpressing cells (bystander killing effect)
7. The half-life of the active drug is long enough for bystander killing effect but short enough to avoid leaking out of tumor cells
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Antibody-Directed Enzyme Prodrug Therapy (ADEPT)
An approach for site-specific delivery of cancer drugs.
Phase One: An antibody-enzyme conjugate is administered which binds to the surface of the tumor cells. The antibody used has been targeted for the particular tumor cell. The enzyme chosen for the conjugate is one that will be used to cleave the carrier group off of the prodrug administered in the next phase.
Phase Two: After the antibody enzyme has accumulated on Phase Two: After the antibody-enzyme has accumulated on the tumor cell and the excess conjugate is cleared from the blood and normal tissues, the prodrug is administered. The enzyme conjugated with the antibody at the tumor cell surface catalyzes the conversion of the prodrug to the drug when it reaches the tumor cell.
ADEPTAdvantages:
1. Increased selectivity for targeted cell
2. Each enzyme molecule converts many prodrug moleculesmolecules
3. The released drug is at the site of action
4. Demonstrated to be effective at the clinical level
5. Concentrates the drug at the site of action
Disadvantages:g1. Immunogenicity and rejection of antibody-enzyme conjugate2. Complexity of the two-phase system and i.v. administration3. Potential for leakback of the active drug
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An example is carboxypeptidase G2 or alkaline phosphatase linked to an antibody to activate a nitrogen mustard prodrug.
II II
Scheme 8.4
N
O
O
IIN
OH
I
carboxypeptidase G2
electron-donating;activates nitrogen mustard
+
HN CO2H
CO2H
L-Glu + CO2
8.19
electron-withdrawing;deactivates nitrogen mustard
Humanization of antibodies minimizes immunogenicity. Note the prodrug-activating enzyme is a bacterial enzyme.
Antibody-Directed Abzyme Prodrug Therapy (ADAPT)
Instead of using a prodrug-activating enzyme, a humanized prodrug-activating catalytic antibody ( b ) b d(abzyme) can be used.
Ideally, the abzyme catalyzes a reaction not known to occur in humans, so the only site where the prodrug could be activated is at the tumor cell where the abzyme is bound.
Antibody 38C2 catalyzes sequential retro aldol and Antibody 38C2 catalyzes sequential retro-aldol and retro-Michael reactions not catalyzed by any known human enzyme.
Found to be long-lived in vivo, to activate prodrugs selectively, and to kill colon and prostate cancer cells.
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Abzyme 38C2 Activation of a Doxorubicin Prodrug
Scheme 8.5
O O O
8.20
O
O
OH
OHCH3O H O
OH
O
NHHO
CH3
OH
O
O
O
O OH
38C2
O
O
OH
OHCH3O H O
OH
O
NHHO
CH3
OH
O
O
O
O
O
H
38C2
O
O
O
OH
OHCH3O H O
OH
O
NHHO
CH3
OH
O
O
O-
-CO2 +H+
retro-aldol retro-Michael
B-
B-
O
O
OH
OHCH3O H O
OH
O
NH2HO
CH3
OH
O
doxorubicin
Gene-Directed Enzyme Prodrug Therapy (GDEPT)
Also known as suicide gene therapyA gene encoding the prodrug-activating enzyme is expressed in target cancer cells under the control of
NNH
OMe
OMe
OMe
Cl
NHO
NMe
N
O2N O
nitroreductase NNH
OMe
OMe
OMe
Cl
NHO
NMe
N
N O
H
HO :
CO
expressed in target cancer cells under the control of tumor-selective promoters or by viral transfection. These cells activate the prodrug as in ADEPT.
O
amino-seco-CBI-TMI8.21
O
NNH
OMe
OMe
OMe
Cl
NH2
O
-CO2+H+
Scheme 8.6
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Prodrug for Stabilityprotection from first-pass effect
Oral administration has lower bioavailability than i v injectioni.v. injection.
propanolol (R = R' = H)8 22
OR'
O NHCH(CH3 )2
R
8.22
prodrug R' =OCCH2 CH2COOH
antihypertension
plasma levels 8 times that with propanolol
Prodrugs for Slow and Prolonged Release1. To reduce the number and frequency of doses
2. To eliminate night time administration
3. To minimize patient noncompliance
4. To eliminate peaks and valleys of fast release (relieve strain on cells)
5. To reduce toxic levels
6. To reduce GI side effects
Long-chain fatty acid esters hydrolyze slowlyIntramuscular injection is used also
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FO
NOR
Cl
haloperidol (R = H)haloperidol decanoate (R = CO(CH2)8CH3)
8.24Sedative/tranquilizer/antipsychotic
O
l lprodrug R' = C(CH2)8CH3 slow release
inject i.m.
Antipsychotic activity for about 1 month
Prodrugs to Minimize Toxicity
Many of the prodrugs just discussed also have Many of the prodrugs just discussed also have lowered toxicity.
For example, epinephrine (for glaucoma) has ocular and systemic side effects not found in dipivaloylepinephrine.p y p p
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Prodrug to Increase Patient Acceptance
The antibacterial drug clindamycin (8.28) is
N HCH3
HN Cl
bitter and not well tolerated by children.
Clindamycin palmitate is not bitter.
clindomycin (R = H)clindomycin phosphate (R = PO3H2)
clindomycin palmitate (R = O(CH2)14CH3)
H O OHO
ORSCH3
OH
2 14 38.28
Either not soluble in saliva or does not bind to the bitter taste receptor or both.
Prodrug to Eliminate Formulation Problems
Formaldehyde is a gas with a pungent odor that is used as a disinfectant. Too toxic for direct use.
methenamine8.30
NN
N
N
CH2O + NH3H+
H3O+
It is a stable solid that decomposes in aqueous acid.
The pH of urine in the bladder is about 4.8, so methenamine is used as a urinary tract antiseptic.
Has to be enteric coated to prevent hydrolysis in the stomach.
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Areas of Improvement for Prodrugs
• site specificity
• protection of drug from biodegradation
• minimization of side effects
Macromolecular Drug DeliveryTo address these shortcomings, macromolecular
drug delivery systems have been developed.
A bi i li k d d i hi h h d i A bipartate carrier-linked prodrug in which the drug is attached to a macromolecule, such as a synthetic polymer, protein, lectin, antibody, cell, etc.
Absorption/distribution depends on the physicochemical properties of macromolecular carrier, not of the drug. Therefore, attain better targeting.
Minimize interactions with other tissues or enzymes. Fewer metabolic problems; increased therapeutic index.
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Disadvantages of Macromolecular Delivery Systems
• Macromolecules may not be well absorbed
• Alternative means of administration may be needed (injection)
• Immunogenicity problemsg y p
Macromolecular Drug Carriers
yxCH2 CH CH2 CH
Synthetic polymers
yx
8.32
OO
O
OOH
Aspirin linked to poly(vinyl alcohol) has about the same potency as aspirin, but less toxic.
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Steric Hindrance by Polymer Carrier
yxCCH2
CH3
CCH2
CH3
poly(methacrylate)
yx
O
O
C=O
O
S=O
C=O
to enhance water solubility
8.34
Otestosterone
No androgenic effectPolymer backbone may be sterically hindering the release of the testosterone.
A spacer arm was added, and it was as effective as testosterone.
x yC
C=O
CH2
C=O
C
CH3
CH2
CH3
spacer arm
Cl-+
O
O
S=OH3 CO
NMe2
O
C O
to enhance water solubility
8.35O
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Poly(α-Amino Acid) Carriers
poly(L-glutamine)
spacerx
O
NH CH C
O
O
OO
O
NH C
O
CH
norethindrone - contraceptive
Slow release over nine months in rats
8.37
O
General Site-Specific Macromolecular Drug Delivery System
Polymer chain
either hydrophilic
Solubilizer spacer Homing device
y por hydrophobic for site specificityDrug
8.38
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Site-Specific Delivery of a Nitrogen Mustard
spacer arm
poly(L-Glu)zyx
CHCH C NHC NH
O
NHCH
O O
C
O
antibody from rabbit antiserum against mouse
water-solubilizing
NH
NClCl
OO
O- NH
Ig
O
against mouse lymphoma cells
All 5 mice tested were alive and tumor free after 60 days (all controls died).
Also, therapeutic index greatly enhanced (40 fold).
8.39
Tumor Cell Selectivity
Tumor cells take up
Drug attached to albumin (R = albumin)NH2
proteins rapidly. Proteins broken down inside cells, releasing the drug.
Shown to inhibit growth of Ectomelia virus in
O
OH
NRO
N
O
HO
mouse liver, whereas free inhibitor did not.
antitumor
OH
cytosine arabinoside (R = H)8.41
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Antibody-Targeted Chemotherapy
O
HO
calicheamicin, except as disulfide instead of trisulfide
Scheme 8.7
NH
O
CH3O
S
O
H polysaccharide
S
O
HN
N
CH3
O
O
HN
Lysantibody
gemtuzumab ozogamicin8.42
RS-
O
NH
O
CH3O
HO
S
O
H polysaccharide
8.43
spacerhumanized
Does not release calicheamicin nonenzymatically.
Exhibits no immune response.
Tripartate Drugs(Self-immolative Prodrugs)
A bipartate prodrug may be ineffective because the linkage is too labile or too stable.g
In a tripartate prodrug, the carrier is not attached to the drug; rather, to the linker.
Therefore, more flexibility in the types of functional groups and linkages that can be used, and it moves the cleavage site away from the carrierthe cleavage site away from the carrier.
The linker-drug bond must cleave spontaneously (i.e., be self-immolative) after the carrier-linker bond is broken.
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Tripartate Prodrugs
Scheme 8.8
Carrier Linker Drugenzyme
DrugLinkerCarrier +
spontaneous
Linker Drug+
Typical Approach
Scheme 8.9
fast
Drug—X- + CH2O
Drug—X—CH2 —O- + RCOOHesteraseDrug—X—CH2 —O—CR
O
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Tripartate Prodrugs of AmpicillinO
NH2
NHS
Poor oral absorption (40%)
E tibi ti d t
ampicillin8.44
NNH2
OCOO-
antibacterial
Excess antibiotic may destroy important intestinal bacteria used in digestion and for biosynthesis of cofactors.
Also, more rapid onset of resistance.
Various esters made were too stable in humans (although they were hydrolyzed in rodents) - thought the thiazolidine ring sterically hindered the esterase.
resistance.
Tripartate Prodrugs of Ampicillin
SNH
O
Ph
SNH
O
Ph
Scheme 8.10
esterase
bacampicillin (R = CH3, R' = OEt)pivampicillin (R = H, R' = t-Bu)
8 45
8.46
..
+ R'COOH
whenR' = OEt
EtOH+ CO2
NH2
N
S
O
OO O
R
R'
O
NH2
N
S
O
OO
R
O
OH
8.45
8.44
R H
98-99% absorbed
Ampicillin is released in < 15 minutes
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enzymecrossesDrug—X
O
Drug—X
O
Drug—X
O
bl d b i oxidation
Reversible Redox Drug Delivery System to the CNS
Scheme 8.11
hydrolysis deactivated
hydrolysis activated
8 49
+ Drug ?XH
enzymehydrolysis
8.488.47
CH3
N
CH3
N
CH3
N+
N+
HOOC
CH3
blood-brainbarrier
oxidation
hydrophilic drug
electron-donating, lipophilic carrier
electron-withdrawing; hydrophilic8.49lipophilic carrier y p
Passive diffusion of 8.47 into the brain; active transport of 8.49out of the brain
If oxidation occurs before it gets into the brain, it cannot cross the blood-brain barrier.
XH of the drug is NH2, OH, or COOH
When the drug is a carboxylic acid, a self-immolative reaction also can be used.
Scheme 8.12
Drug—COO-
fast —CH2O
Drug— —O—CH2 —O-esterase
8.50
C
OHOC
O
carrier+Drug C OCH2 O C carrier
O O
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Example of Redox Drug DeliveryAntibody generation in the brain is not significant.
β-Lactams are too hydrophilic to cross the blood-brain barrier effectively.
8.51
O
HN
ON
SR
OO
O
N
Me
O
enzymatic
oxidation
N
Me
O
HN
ON
SR
OO
O
O
esterase
N
Me
O
OO
HN
ON
SR
OO O
-CH2OO
HN
ON
SR
OO-
8.49High concentrations of β-lactams delivered into brain.
Scheme 8.13
Tripartate Prodrug for Delivery of Antibacterials
Permeases are bacterial transport proteins for uptake of peptides.p p
+..
+1. permease
+
CH3
OCH3
HN
NH
N
COO-
N
H3N
HN F
O
O COO-H3N
H2N
O
F
O
COO-
O
2. peptidase
Scheme 8.14
+NH4 +
++
8.53HN
NH
F
O
O
COO-H2N
COO-
H
H
Only L,L-dipeptides are active
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Mutual ProdrugsA bipartate or tripartate prodrug in which the carrier is a synergistic drug with the drug to which it is linked.
Antibacterial β l i i
NH2
PhNH S
NON
O
O
S
O
OO
Antibacterial ampicillin
β-lactamase inactivatorpenicillanic acid sulfone
sultamicillin8.59
O O O
Hydrolysis gives 1:1:1 ampicillin : penicillanic acid sulfone : formaldehyde
Ideal Mutual Prodrugs
• Well absorbed
• Both components are released together • Both components are released together and quantitatively after absorption
• Maximal effect of the combination of the two drugs occurs at 1:1 ratio
• Distribution/elimination of components are similar
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Bioprecursor Prodrugs
Carrier-linked prodrugs largely use hydrolytic activationactivation
Bioprecursor drugs mostly use oxidative or reductive activation
Th b li ll i d lk l i The metabolically-activated alkylating agents discussed in Chapter 6 are actually examples of bioprecursor prodrugs.
Protonation ActivationDiscovery of Omeprazole
Cimetidine and ranitidine (Chapter 3) reduce Cimetidine and ranitidine (Chapter 3) reduce gastric acid secretion by antagonizing the H2
histamine receptor.
Another way to lower gastric acid secretion is by inhibition of the enzyme H+ K+-ATPase (also inhibition of the enzyme H ,K ATPase (also called the proton pump), which exchanges protons for potassium ions in parietal stomach cells, thereby increasing stomach acidity.
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Lead Discovery
Lead compound found in a random screen.
8.60
N
S
NH2
Liver toxicity observed thought to be because of the thioamide group.
Lead ModificationRelated analogs made, and 8.61 had good antisecretory activity.
8 61
NS
NH
N
Modification gave 8.62 with high activity.
8.62
NS
NH
N
8.61
The sulfoxide (8.63) was more potent but it blocked
timoprazole8.63
NS
NH
NO
The sulfoxide (8.63) was more potent, but it blocked iodine uptake into the thyroid.
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Lead Modification (cont’d)
Modification of 8.63 gave 8.64 having no iodine blockage activity.
NS
NH
NO
CH3
CH3
CO2CH3
g y
Picoprazole shown to be an inhibitor of H+,K+-ATPase. SAR of analogs indicated electron-donating groups on the pyridine ring were
picoprazole8.64
H
SN
OCH3
OCH3
OCH3
H3 C
the pyridine ring were favorable. Increased inhibition of H+,K+-ATPase.Best analog was omeprazole (8.65).
omeprazole8.65
NS
NH
The pKa of the pyridine ring of omeprazole is about 4, so it is not protonated and able to cross the secretory canaliculus of the parietal cell. The pH inside the cell is below 1, so this initiates the protonation reaction below.
CH3
OCH3
H3 C CH3
OCH3
H3 C CH3
OCH3
H3 C CH3
OCH3
H3 CScheme 8.16
omeprazole8.65
N
SHN
N
O
OCH3
..
H+
N
SHN
NO
OCH3
H
N
SHN
NOH
OCH3
..N
SN N
OCH3
8.66
S
-H2 O
+H+
N
SN NH
CH3
OCH3
H3 C
OCH3
S
Formation of 8.66 leads to covalent attachment.Omeprazole also inhibits isozymes of carbonic anhydrase, another mechanism for lowering gastric acid secretion.
2009-09-17
37
Hydrolytic ActivationHydrolysis can be a mechanism for bioprecursor prodrug activation, if the product requires additional activation
K2CO3/RXS
S+
O
NH N
SO-
O OHM
Me
N N
SMe
S+
O
O-O
S
R
MeHO
activation.Scheme 8.17
leinamycin8.70 8.71
O
O OHMe
Me HO OMe
HO
antitumor agent prodrugs of leinamycin
N N
SMe
S+
O
O-O
S
MeHO
OO
O
Me
HO-
N N
SMe
S+
O
O-O
S-
MeHO
SS+
O
NH
N
SO-
O OHMe
Me
DNA
Hydrolysis of these analogs gives an intermediate that reacts further to the activated form.
8.72
OMe
O OMe O
O OHMe
Me
O
O
O
8.73
O
O
DNAcleavage
O SMe
HO2 C
increased stability over leinamycin
this was synthesized
and gave 8.74 as well
DNA NH
N
O
8.74
O
O
S
MeHO
HO2 C
MeHO
yas DNA cleavage
Scheme 8.18
2009-09-17
38
Elimination Activation
OCF3
B:O
CF3
Scheme 8.19
NO CH3
NH
H
leflunomide8.75
CN
HO CH3
O
NH
8.76BH
rheumatoid arthritis drug
potent inhibitor of dihydroorotate dehydrogenaserheumatoid arthritis drug dehydrogenase
Inhibition of dihydroorotate dehydrogenase blocks pyrimidine biosynthesis in human T lymphocytes.
Oxidative ActivationN-Dealkylation
Sedative 8.20N
CH3N
CH3N
CH3
..P450P450
Cl
N N
NCH3
O
X
CH3
Cl
N N
NH
O
X
CH3
Cl
N NNH2
O
X
NNCH3
NNCH3
..NH
NN
ClHO X
N
N
Cl
X
alprazoalam (X = H)triazolam (X = Cl)
8.77
-H2 O
2009-09-17
39
O-Dealkylation
Analgesic activity of phenacetin is a result of O-dealkylation to acetaminophen.
CH3HN
O
phenacetin (R = CH2CH3)acetaminophen (R = H)
8.78
OR
Oxidative DeaminationNeoplastic (cancer) cells have a high concentration of phosphoramidases, so hundreds of phosphamide analogs of nitrogen mustards were made for selective activation in these cells.
P-450HN O
HN O
HO:
H NH2
OScheme 8.21
8.84
HPO4= + NH3 + spontaneous
orphosphoramidase
8.82 8.83
+
B:
8.81
P 450
8.80cyclophosphamide8.79
OP
O
N O
Cl
PClO
N
Cl
ClO
P2
O
N
Cl
ClH
-O PH2N
O
H
O
N
Cl
ClHN
Cl
Cl
Cyclophosphamide was very
Scheme 8.21
+
8.868.85
DNA DNA
8.84
HN
N N
N
H2NDNA
O
HN
N
HN
N
OH N
H2N
O HN
OH
Cyclophosphamide was very effective, but it required liver homogenates (contains P450) for activation. Therefore oxidation is required, not hydrolysis. isolated
2009-09-17
40
N-Oxidationidentified
procarbazine
P450
8.88B—H+
CH3NHNHCH2 CNHCHMe2
O
CH3N=N—CH CNHCHMe2
O
H
CH3 NHNHCH2 CNHCHMe2
O
HO
-H2 O
advanced Hodgkin’s disease
+
H
procarbazine8.87 B:
8.89
H2OCH3N-NH2 + OHC CNHCHMe2
O
CH3N-N=CH CNHCHMe2
O
HN N
CH3O
N
H
CH3N=NH
CH3-N+
DNA HN N
CH3O
identifiedScheme 8.22
HN
N NH2N
DNA
3
CH3 + N2
DNA
8.90
HN
N NH2N
N-Oxidation
Pralidoxime chloride is an antidote for nerve poisons.
N OH
It reacts with acetylcholinesterase that has been inactivated by organophosphorus toxins.
+
pralidoxime chloride8.91
Cl- N
N
CH3
OH
2009-09-17
41
To increase the permeability of pralidoxime into the CNS, the pyridinium ring was reduced (8.92).
8 92
NN
CH3
OH
+Cl-
NN
CH3
OH
oxidation into brain
8.92
pralidoxime chloride8.91
Similar to the reversible redox drug delivery strategy for getting drugs into the brain by attaching them to a dihydronicotinic acid, hydrophobic 8.92 crosses the blood-brain barrier; oxidation to 8.91prevents efflux from brain.
Mechanism of Acetylcholinesterase
Scheme 8.23
+ :B
H2O
+
OCH3
OHB
Me3N—CH2CH2—OO
CH3
OB
H
H
Me3N—CH2CH2—OH
B:
Trp
Phe TrpTrp
PheTrp
Me3NCH2CH2OH + CH3 COOH+
H2O
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42
Inactivation of Acetylcholinesterase by Diisopropyl Phosphorofluoridate
Scheme 8.24affinity labeling agent
8.93
+ :BO
B
H
H
Trp
Phe Trp
OP
OF
O
OB
Trp
Phe Trp
OP
O
O
HB
irreversible inhibitionirreversible inhibition
Inactivation prevents degradation of the excitatory neurotransmitter acetylcholine. Accumulation of acetylcholine causes muscle cells in airways to contract and secrete mucous, then muscles become paralyzed.
Reactivation of Inactivated Acetylcholinesterase by Pralidoxime
Scheme 8.25
pralidoximeO
B
Trp
Phe Trp
OP
O
O
HBO
B
Trp
Phe Trp
OP
O
O
HB
NMe
NO:
H
ON
NO
Me
P
O
OHBH
Trp
Phe Trp:B
NON
Me
P
OO
OO
2009-09-17
43
Temporary inhibition of acetylcholinesterase enhances cholinergic action on skeletal muscle.
O
Scheme 8.26
+ :B
H2O
+
ONMe2
O HB
OBH
H B:
TrpPhe Trp
Trp
PheTrp
O
O
NMe2
Me3N OHMe3N
slow
neostigmine8.94
Used for the neuromuscular
covalent, but reversible i hibiti
OHMe3N+ CO2 + Me2NH
disease myasthenia gravisinhibition
Reversible (noncovalent) inhibitors of acetylcholinesterase, such as donepezil and tacrine are used for Alzheimer’s disease. Enhances
t i i i l d i neurotransmission involved in memory.
H3CO
H3CO
O
N
HClN
NH2
. HCl
donepezil hydrochloride8.95
. HCl
tacrine hydrochloride8.96
. HCl
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S-Oxidation
Poor oral bioavailability of brefeldin A. Converted to Michael addition sulfide prodrug (8.98). S-Oxidation
d li i i i b f ldi Aand elimination gives brefeldin A.Scheme 8.27
O
O
CH3HO
HO
H
H
O
O
CH3HO
HO
H
H
RS HO
O
CH3HO
HO
H
H
RSHO
HH
:B
[O]
brefeldin A8.97 8.98
8.99
RSH
antitumor, antiviral agent
-RSOH
8.99
Aromatic HydroxylationCyclohexenones as prodrugs for catechols
Scheme 8.28
aromatic hydroxylationoxidation next to
O
N
8.100
P450
O
N -H2 O
O
N
OH
N
P450
HO
oxidation next to sp2 carbonyl
8.101
OH
N
HO
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45
Alkene Epoxidation
O
carbamazepine8 102
N
O NH2
8 103
N
O NH2
8.102 8.103active anticonvulsant agent
Transamination
Stimulation of pyruvate dehydrogenase results in a change of myocardial metabolism from fatty acid g y yto glucose utilization.
Glucose metabolism requires less O2 consumption.
Therefore, utilization of glucose metabolism would be beneficial to patients with ischemic heart be beneficial to patients with ischemic heart disease (arterial blood flow blocked; less O2
available).
2009-09-17
46
COOH
O
Arylglyoxylic acids (8.104) stimulate pyruvate dehydrogenase, but have a short duration of action.
8.104
R
Oxfenicine (8.105, R = OH) is actively transported and is transaminated (a PLP aminotransferase) in the heart to 8.104 (R = OH).
NH( )
oxfenicine (R = OH)8.105
COOH
NH2
R
COOH
Reductive ActivationAzo Reduction
Scheme 8.29
+
sulfasalazine8.106
NNHSO2 N=N OH
H2N OH
COOH
NNHSO2 NH2
ulcerative colitis
Anaerobic cleavage by bacteria in lower bowel
sulfapyridine8.108
8.107
For inflammatory bowel disease
Causes side effects
2009-09-17
47
To prevent side effect by sulfapyridine a macromolecular delivery system was developed.
n
SO2
NH
poly(vinylamine)
Not absorbed or
8.109
N
SO2
N
CO2Na
OH
spacer
Not absorbed or metabolized in small intestine.
CO Na
NH2
CO2Na
OHReleased by reduction at the disease site.
Sulfapyridine is not released (still attached to polymer).
More potent than sulfasalazine.
Azido Reduction
N
N N
N
R
vidarabine (R = NH2)8.110
N
OHO
HO
OH
antiviral drug
Vidarabine is rapidly deaminated by adenosine deaminase. 8.110, R = N3 is not a substrate for adenosine deaminase and also can cross the blood-brain barrier for brain infections.
2009-09-17
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Sulfoxide Reduction
CH3
CO2HF
sulindac
SCH3
O
sulindac8.111
anti-arthritis
Sulindac is inactive in vitro; the sulfide is active in vitro and in vivo.
Sulindac is an indane isostere of indomethacin, which was designed as a serotonin analog.
The 5-F replaced the 5-OMe group to increase analgesic properties.
The p-SOCH3 group replaced p-Cl to increase water solubilityThe p SOCH3 group replaced p Cl to increase water solubility.
CH3
CO2HF
NCH3
CO2HMeO
O HO
NH2
sulindac8.111
SCH3
Oindomethacin
8.112
Cl NH
serotonin
2009-09-17
49
Disulfide ReductionTo increase the lipophilicity of thiamin for absorption into the CNS.
GSH..
N
OH
N
OHScheme 8.30
+8.113
H
N
N
NH2
N
HCH3
SO
O
N
N
NH2
N
HCH3
S-
O
OH
S
B
nonenzymatic
+
thiamin8.114
N
N
NH2
N
SCH3
N
N
NH2
N:S
CH3
OH
OH
OH
poorly absorbed into CNS
primaquine8.115
N
CH3O
HNNH2
To diminish toxicity of primaquine and target it for cells with the malaria parasite, a macromolecular drug delivery system was designed.
8.115
serumalbumin
lactose
N
CH3O
HN
O
NH +
SSNH
antimalarial, toxic Intracellular thiol much higher than in blood; selective reduction inside the cell
lactose8.116
NH3+H
primaquine for improved uptake in liver
Therapeutic index of 8.116 is 12 times higher than 8.115 in mice.
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Nitro Reduction
HN
OF
OCl
HN
OF
OCl
HN
OF
O
Cl
Scheme 8.32
NO
OO
HO
P
O
N
H3 C
O
O2N
bioreduction NO
OO
HO
P
O
N
H3 C
O
NHHO..
NO
O
O
HO
P
O-
N
H3 C
..
HN
N
O
OO
F
P
O
N
HN
N
O
OO
F
P
OH2O
HN
N
O
OO
F
P
O
O
8.118 8.119
8.120
NO
O
HO
P
O-
N
H3 C
NO
O
HO
P
O
2NO
OO
HO
P
O-
-O
8.121
Mechanism-based inactivator of thymidylate synthase
Nucleotide Activation
O=O3PO O O
N
SH
Scheme 8.33
hypoxanthine-guaninephosphoribosyltransferase
6-mercaptopurine8.122
N
N NH
N
SH
HO
O—P—O—P—O-
OH O- O-
N
N N
N
O
HO OH
=O3PO
8.123Anti-leukemia drugInhibits several enzymes in the purine nucleotide biosynthesis pathway.
2009-09-17
51
Phosphorylation Activation
HN
N N
N
O
H2NRO
HOO
NH2N
O
NHN
N
acyclovir (R = H)8.124
O
8.125
HO
antiviral 2′-deoxyguanosine
Resembles structure of 2′-deoxyguanosine
viral thymidine kinaseR = PO3
=
viral guanylate kinase
viral thymidine kinase
R = P2O6-3
viral phosphoglycerate kinaseR = P3O9
-4
Uninfected cells do not phosphorylate acyclovir (selective toxicity)
Acyclovir triphosphate is a substrate for viral α-DNA polymerase but not for normal α-DNA polymerase
Incorporation into viral DNA leads to a dead end Incorporation into viral DNA leads to a dead-end complex (not active). Disrupts viral replication cycle and destroys the virus.
Even if the triphosphate of acyclovir were released, it is too polar to be taken up by normal cells.
High selective toxicity
2009-09-17
52
Resistance to Acyclovir
Modification of thymidine kinaseModification of thymidine kinase
Change in substrate specificity for thymidine kinase
Altered viral α-DNA polymerase
Only 15-20% of acyclovir is absorbed
Therefore, prodrugs have been designed to increase oral absorption.
Hydrolyzes here Prodrug for
a prodrug
HOO
NH2N
NH2
NN
N
adenosine deaminase
acyclovir
8.126
O
2009-09-17
53
Hydroxylates here
N
N
N
H N
xanthine oxidase
8.127
N NH2N
OHO
acyclovir
This prodrug is 18 times more water soluble than acyclovir.
A bipartate carrier-linked prodrug of acyclovir, the L-valyl ester of acyclovir, has 3-5 fold higher oral bioavailability with the same safety profile.
O
HN
N N
N
O
H2N
OO
O
H2N
valaciclovir8.128
O
2009-09-17
54
An analog of acyclovir whose structure is even closer to that of 2′-deoxyguanosine is ganciclovir.
O
NHN
HOO
NH2N
HN
N
HO
More potent than acyclovir against human cytomegalovirus.
ganciclovir8.129
O
Two carbon isosteres of ganciclovir are available.
NH2N
O
NHN
N NH2N
NN
N
penciclovir8.130
HO
HO
famciclovir8.131
AcO
AcOC in place of O
C in place of O
Better oral absorption Better oral absorption than penciclovirConverted to penciclovir rapidly
2009-09-17
55
Sulfation ActivationActivity of minoxidil requires sulfotransferase-catalyzed sulfation to minoxidil sulfate.
OR
N
N NH2H2N
N
minoxidil (R = )
Inhibitors of the sulfotransferase inhibit the activity of minoxidil, but not minoxidil sulfate.
hair growth
minoxidil (R = )minoxidil sulfate (R = SO 3
- )8.132
Decarboxylation Activation
An imbalance in the inhibitory neurotransmitter dopamine and the excitatory neurotransmitter
t l h li d t di d acetylcholine produces movement disorders, e.g. Parkinson’s disease.
In Parkinson’s there is a loss of dopaminergic neurons and a low dopamine concentration.
Dopamine treatment does not work because it cannot cross blood-brain barrier, but there is an active transport system for L-dopa (levodopa, 8.133, R = COOH).
2009-09-17
56
HO
HONH2
RH
levodopa (R = COOH)8.133
R
After crossing blood-brain barrier
L-aromatic amino acid decarboxylase (PLP)
dopamine (R = H)
Does not reverse the disease, only slows progression.
Combination Therapy
Monoamine oxidase B (MAO B) degrades dopamine in the braindopamine in the brain.
Therefore, a MAO B-selective inactivator is used to protect the dopamine - selegiline (L-deprenyl).
Peripheral L-aromatic amino acid decarboxylase destroys >95% of the L-dopa in the first pass. Maybe only 1% actually gets into brain.
2009-09-17
57
To protect L-dopa from peripheral (but not CNS) degradation, inhibit peripheral L-aromatic amino acid decarboxylase with a charged molecule that does not cross the blood-brain barrier.
HO
carbidopa8.134
H3 C COO-
NHNH3+
HO
HO
benserazide8.135
HH
HO
HON N
OHO NH2
OH
(used in U.S.)
Selectively inhibits peripheral L-amino acid decarboxylase.
The dose of L-dopa can be reduced by 75%.
(used in Europe and Canada)
Selective Inactivation of Brain Monoamine Oxidase A
Earlier we found that inactivation of brain MAO A has an antidepressant effect, but a cardiovascular side effect occurs f i ti ti f i h l MAO A
F
from inactivation of peripheral MAO A.
8.136 (R = COOH) is actively transported into the brain, where L-aromatic amino acid decarboxylase converts it to 8.136 (R = H), a selective MAO A mechanism-based inactivator. Carbidopa protects 8.136 (R = COOH) from decarboxylation outside of the brain
8.136
OH
NH2
R
decarboxylation outside of the brain.
2009-09-17
58
L-γ-glutamylCOO-OH OH
Selective Delivery of Dopamine to KidneysDopamine increases renal blood flow.
Prodrugs were designed for selective renal vasodilation.
Scheme 8.34
+
L-aromatic amino aciddecarboxylase
+
Glu
L γ glutamyltranspeptidase
8.137
+
COO-
O
NH3
COO-
HN OH
COO-
OHNH3
OHNH3
L-γ-glutamyl-L-dopa
Dopamine accumulates in the kidneys because of
L-dopa
OH
3
high concentrations of L-γ-glutamyltranspeptidase and L-aromatic amino acid decarboxylase there.
Example of a carrier-linked prodrug of a bioprecursor prodrug for dopamine.