Transcript Document

Chapter 5
prodrugs
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前药
5.1 The term prodrug
Prodrug is a pharmacologically inactive compound that is converted into an active
drug by a metabolic biotransformation.
A prodrug also can be activated by a nonenzymatic process such as hydrolysis, but
in this case the compounds generally are unstable and may cause stability problems.
The prodrug to drug conversion can occur before absorption, during absorption,
after absorption, or at a specific site in the body. In the ideal case a prodrug is
converted to the drug as soon as the desired goal.
Prodrugs and soft drugs are opposite. Whereas prodrugs are inactive compounds
that require a metabolic conversion to the active form, a soft drug is active and uses
metabolism as a means of promoting excretion.
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5.2 Purpose of prodrug design
Prodrug design is a lead modification approach that is used to correct a flaw
in a drug candidate.
Aqueous Solubility
Absorption and Distribution
Site Specificity
Instability
Prolonged Release
Toxicity
Poor Patient Acceptability(unpleasant taste or odor, gastric irritation)
Formulation Problems
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5.3 Types of Prodrugs
1）Carrier-linked prodrug(载体连接型前药）
A compound that contains an active drug linked to a carrier group that can be removed
enzymatically, such as an ester, amide which is hydrolyzed to an active carboxylic acid,
alcohol or amine. Carrier group must be labile enough to released active drug in
vivo.The carrier group must be nontoxic and biologically inactive.
bipartate prodrug(二元前药） comprised of one carrier attached to the drug.
modification
D
active drug
+
C
DC
carrier
prodrug
metabolism
D
active drug
+
C
carrier
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tripartate prodrug（三元前药）: a carrier is connected to drug with a linker
D +
active drug
Ln +
linker
modification
C
metabolism
D-Ln-C
prodrug
carrier
D +
active drug
L
linker
D- Ln +
inactive
metabolism
C
carrier
D - L + L1 + L2 + L3 ......
mutual prodrug（协同前药） consists of two, usually synergistic, drugs
attached to each other directly or by a linker (also be called twin drug ,孪药).
D1(P1) + D2(P2)
linking
D1(P1) - D2(P2)
active drug or
pharmacophore
D1(P1)
+
L +
linker
metabolism
prodrug
D2(P2)
linking
D1(P1) - L - D2(P2)
D1
+
D2
active drug
metabolism
D1
+
D2
+
L
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2）bioprecursor prodrug（生物前体型前药）
A compound that is metabolized into a new compound which is the active principle
or which can be metabolized further to the active drug.
Di
metabolism
inactive
Da
active drug
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5.4 Carrier-Linked Prodrugs
An ideal drug carrier
①protect the drug until it is at the site of action;
②localizethe drug at the site of action;
③allow for release of the drug chemically or enzymatically;
④minimize host toxicity;
⑤be biodegradable, biochemically inert, and nonimmunogenic;
⑥be easily prepared inexpensively;
⑦be chemically and biochemically stable in its dosage form.
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1） Carrier-Linked Bipartate Prodrugs
① Prodrugs for Increased Water Solubility
R'O
O
Me
HO
Me
OH
O
R
prednisolone (R = R’ = H)(泼尼松龙）
poorly water-soluble
methylprednisolone (R = CH3, R’ = H)
methylprednisolone sodium succinate (R = CH3, R’ = COCH2CH2CO2Na)
prednisolone phosphate (R = H, R’ = PO3Na2)
water-soluble
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②Prodrugs for Improved Absorption and Distribution
Both fluocinolone acetonide and fluocinonide are prodrugs used for inflammatory
and pruritic manifestations（瘙痒症）. Once absorbed through the skin, an
esterase releases the drug(fluocinolone)
RO
O
Me
HO
Me
Me
O
Me
O
F
O
F
fluocinolone acetonide (R = H)（肤轻松）
fluocinonide (R = COCH3)（醋酸肤轻松）
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A prodrug for the antiglaucoma（抗青光眼） drug epinephrine（地
匹福林）
RO
OH
RO
NHCH3
dipivefrin (R = Me3CCO)
epinephrine (R = H)（肾上腺素）
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③ Prodrugs for Site Specificity
a. GABA
progabide（普罗加比）
Increasing the brain concentration of the inhibitory neurotransmitter γ -aminobutyric
acid (GABA) results in anticonvulsant activity. However, GABA is too polar to
cross the blood–brain barrier, so it is not an effective anticonvulsant drug.
OH
N
F
O
NH2
H2N
COOH
GABA
Progabide
Cl
progabide is an effective lipophilic analog of GABA that crosses the blood–
brain barrier, releases GABA inside the brain, and shows anticonvulsant
activity.
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b. Antibody-directed enzyme prodrug therapy(ADEPT)
I
I
N
I
N
I
carboxypeptidase G2
H
N
O
O
CO2H
L-Glu
CO2
OH
CO2H
electron-withdrawing:
deactivate nitrogen mustard
electron-donating:
activates nitrogen mustard
An example of ADEPT is the delivery of a nitrogen mustard as a glutamic acid
conjugate after administration of a humanized monoclonal antibody conjugated
to the bacterial enzyme carboxypeptidase G2 .
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④ Prodrugs for Stability
propanolol (R = R’ = H)（普奈洛尔）
NHCH(CH 3)2 O-glucuronide ( R=H,OR’=glucuronide), metabolite
O
OR'
p-hydroxypropranolol( R =OH,R’=H), metabolite
O-glucuronide(R=OH,OR’=glucuronide)
R
The hemisuccinate ester of propranolol
( R =H,R’=COCH2CH2COOH)
Some prodrugs protect the drug from the first-pass effect .Propranolol is a widely
used antihypertensive drug, but because of first-pass elimination, an oral dose has a
much lower bioavailability than does intravenous injection. The major metabolites are
propranolol O-glucuronide. The hemisuccinate ester of propranolol was prepared to
block glucuronide formation; following oral administration of propranolol
hemisuccinate, the plasma levels of propranolol were eight times greater than when
propranolol was used.
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⑤ Prodrugs for Slow and Prolonged Release
Haloperidol is a potent, orally active central nervous system depressant, sedative,
and tranquilizer. However, peak plasma levels are observed between 2 and 6 h
after administration. The ester prodrug haloperidol decanoate is injected
intramuscularly as a solution in sesame oil, and its antipsychotic activity lasts for
about 1 month.
O
I
OR
N
Cl
haloperidol (R=H)（氟哌啶醇）
haloperidol decanoate (R = CO(CH2)8CH3)
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⑥Prodrugs to Minimize Toxicity
Side effects associated with the use of aspirin are gastric irritation and
ulcerogenicity associated with aspirin use may result from an accumulation of the
acid in the gastric mucosal cells. Esterification of aspirin and other nonsteroidal
anti-inflammatory agents greatly suppresses gastric ulcerogenic activity.
Esters of N,N-disubstituted 2-hydroxyacetamides were found to be chemically
highly stable, but were hydrolyzed very rapidly by pseudocholinesterase（伪胆碱
酯酶） in plasma
O
OR
O
CH3
O
aspirin (R = H)
N,N-disubstituted 2-hydroxyacetamides
( R=CH2CONR1R2)
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⑦Prodrugs to Encourage Patient Acceptance
A fundamental tenet in medicine is that in order for a drug to be effective, the
patient has to take it! Painful injections and unpleasant taste or odor are the
most common reasons for the lack of patient acceptance of a drug.
CH 3
H
N
H
O
HO
H
N
Cl
O
OH
SCH 3
OR
clindamycin (R = H)(克林霉素) :causes pain on injection,
a bitter taste orally
clindamycin phosphate (R = PO3H2): well tolerated on injection
clindamycin palmitate (R = CO(CH2)14CH3): no bitter taste orally
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⑧Prodrugs to Eliminate Formulation Problems
Formaldehyde (CH2O) is a flammable, colorless gas with a pungent odor that is
used as a disinfectant. Solutions of high concentrations of formaldehyde are
toxic. Consequently, it cannot be used directly in medicine.
However, the reaction of formaldehyde with ammonia produces a stable
adamantane-like solid compound, methenamine(孟德立胺, trade name is
urotropine乌洛托品 ). In acidic pH media, methenamine hydrolyzes to
formaldehyde and ammonium ions. Because the pH of urine in the bladder is
mildly acidic, methenamine is used as a urinary tract antiseptic.To prevent
hydrolysis of this prodrug in the acidic environment of the stomach, the tablets
are enteric coated.
N
N
N
Methenamine
N
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2) Tripartate Prodrugs
Bipartate prodrugs may be ineffective because the prodrug linkage is too labile
(e.g., certain esters) or too stable (because of steric hindrance to hydrolysis).
In a tripartate prodrug the carrier is not connected directly to the drug, but rather
to a linker that is attached to the drug. This allows for different kinds of
functional groups to be incorporated for varying stabilities, and it also displaces
the drug farther from the hydrolysis site, which decreases the steric interference
by the carrier.
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The double ester
The drug-linker connection, however, must be designed so that it cleaves
spontaneously (i.e., is self immolative 自脱落) after the carrier has been
detached. One approach to accomplish this has been termed the double
prodrug or, in the case where X = COO, the double ester concept, generalized
in Scheme . (X = COO, O, NH).
Drug
R
esterase
O C
O
X CH2
Drug
H2
X C O
RCOOH
f ast
Drug
X
CH 2O
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The example of Tripartate Prodrugs
①Ampicillin is poorly absorbed when administered orally. Because only 40%
of the drug is absorbed, 2.5 times more drug must be administered orally than
by injection.
Alipid-soluble prodrug of ampicillinwould be a useful approachto increase
absorption of this drug. However, although various simple alkyl and aryl esters
of the thiazolidine carboxyl group are too stable in humans to be
therapeutically useful. A solution to the problem was the construction of
a“double ester,” an acyloxymethyl ester.
O
O
Ph
Ph
NH
S
NH2
esterase
NH
S
NH 2
N
R'COOH
N
O
O
O
O
O
R
O
bacampicillin(R=CH 3,R'=OEt)
pivampicillin(R=H,R'=t-Bu)
8.45
R'
O
OH
O
8.46
when:
R'=OH
R
O
R
EtOH + CO 2
H
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②The prodrug to cross the blood–brainbarrier passively
(a dihydropyridine delivery system)
O
Drug
cross bloodbrain barrier
X
O
Drug
O
enzyme
X
N
CH3
N
CH3
Drug
X
oxidation
HOOC
N
CH3
enzyme
hydrolysis
N
CH3
Drug
XH
Prodrug overall sufficiently lipophilic to cross the blood–brain barrier passively.
Once inside the brain, the lipophilic carrier is converted enzymatically into a highly hydrophilic
species pyridinium ion prevents the drug from escaping out of the brain because it becomes
charged.
Any oxidation occurring outside of the brain produces a hydrophilic species that can be rapidly
eliminated from the body .
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A tripartate example of this approach is the brain delivery of β-lactam
antibiotics for the possible treatment of bacterial meningitis(脑膜炎）.
H
N
R
S
esterase
O
N
O
H
N
R
O
O
O
O
O
H
N
N
Me
-CH 2O
O
O
O
N
Me
esterase
S
N
O
O
O
8.51
R
O
N
O
oxidation
O
S
O
H
N
R
S
O
N
O
O
O
O
O
N
Me
Because β-lactam antibiotics are hydrophilic, they enter the brain very
slowly, and they are actively transported out of the brain back into the
bloodstream. Therefore, they are not as effective in the treatment of brain
infections as elsewhere.
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3) Mutual Prodrugs
When it is necessary for two synergistic drugs to be at the same site at the same
time, a mutual prodrug approach should be considered. A mutual prodrug is a
bipartate or tripartate prodrug in which the carrier is a synergistic drug with the
drug to which it is linked.
①Sultamicillin(舒他西林)
O
O
NH
HO
OH
O
S
S
N
NH 2
N
O
O
COOH
COOH
克拉维酸
O
Ph
N
potassium clavulanate
amoxicillin
NH
NH2
O
S O
S
N
O
O
O
O
O
O
O
COOR
penicillanic acid sulf one(R=H)
青霉烷砜酸
β-lactamase inhibitor
Sultamicillin(舒他西林)
N
O
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②Aspirin + Paracetamol
COO
Benorilate
NHCOCH3
OCOCH 3
③Ranitidine Bismuth Citrate,RBC
O
O
O
C
O
O
CHNO2
(H 3C)2NH 2C
O
S
N
H
NHCH 3
HO
Bi +3
O
H2- receptor antagonists
gastric mucosa protective agent
Helicobacter pylori (HP) inhibitor
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5.5 Bio precursor Prodrugs
Carrier-linked prodrugs rely largely on hydrolysis reactions for their effectiveness.
bioprecursor prodrugs mostly utilize either oxidative or reductive activation
reactions. The examples given below are arranged according to the type of
metabolic activation reaction involved.
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1) Proton Activation:
OCH3
OCH3
H3C
H3C
CH3
OCH3
CH3
H3C
CH3
N
N
S O
HN
N
N
S
HN
N
H+
N
H
OCH3
OCH3
OCH3
OCH3
OCH3
H3C
H3C
CH3
H2O
N
N
-S
N
S
HN
O
S
OCH3
CH3
S S
N
+ H+
N
NH
OCH3
OH
Omeprazole is a relatively
weak base, having a pKa of
only about 4. Therefore, the
pyridine ring is not protonated
at physiological pH, so it is
lipid permeable and able to
diffuse into the parietal cell.
However, the pH in the
parietal cell is below 1, so
omeprazole becomes
protonated inside the c parietal
ell, where it becomes trapped,
then undergoes a protoninitiated transformation to
active form, which reacts
covalently with a cysteine
residue of H+,K+-ATPase
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2) Elimination Activation
The rheumatoid arthritis drug leflunomide (来氟米特) is an immunomodulatory
agent shown to inhibit pyrimidine biosynthesis in human T lymphocytes by
blocking the enzyme dihydroorotate dehydrogenase(二氢乳清酸脱氢酶). Whereas
leflunomide shows no inhibitory effect on dihydroorotate dehydrogenase at 1μM
concentration, its metabolite, is a potent inhibitor (Ki 179nM).Isoxazoles are
known to undergo facile elimination to nitriles.
B:
O
H
N
+B
O
H
N
H
CH3
CF3
N
O
C
HO
N
H
CH3
CF3
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3) Oxidative Activation
cyclophosphamide is a prodrug
requiring an oxidative
mechanism. The activation
mechanism is believed to be that
shown in Figure
O
H 2N
NH O
P
O N
Cl
HOOC
O
Cl
NH O
P
O N
P450
Cl
cyclophosphamide
HPO42+
in normal cells
HO
Cl
NH3
O
Cl
Cl
spontaneous
Cl
or
phosphoramidase
H
H2N
O
B
H2N O
P
O N
O
Cl
P
H
Cl
HN
Cl
N
Cl
in normal cells
NH O
P
O N
O
P
N
Cl
O
Cl
Cl
H
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4) Reductive Activation
①Azo Reduction
The prodrug was azo linked at the 5-position through a spacer to
poly(vinyl amine) The advantages of this polymeric drug delivery
system are that it is not absorbed or metabolized in the small intestine.
The water-soluble polymer-linked drug was more potent than in the
guinea pig ulcerative colitis model.
COOH
N
O
NHS
O
N N
OH
a
sulfasalazine
N
SO2
柳氮磺吡啶
COOH
H2N
OH
N
O
NHS
O
CO2Na
NH2
N N
OH
polymeric drug delivery system
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②Azido Reduction
Vidarabine (阿糖腺苷) was originally discovered as an antitumor agent,
then later it was shown to be active against herpes simplex virus(单纯疱疹
病毒） types 1 and 2. However, the clinical use of vidarabine is limited
because of its rapid deamination by adenosine deaminase and its poor
aqueous solubility.
9-(β -D-Arabinofuranosyl)-6-azidopurine, the 6-azido analog of
vidarabine, however, is not a substrate for adenosine deaminase, and it is
considerably more stable in vivo. the half-life for the prodrug is 7-14 times
higher than for vidarabine administered directly.
N3
NH2
N
N
N
N
HO
HO
CYP450-catalyzed
N
N
reduction
O
N
N
OH
9-(¦Â-D-Arabinofuranosyl)-6-azidopurine
HO
O
HO
OH
Vidarabine
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5) Nucleotide Activation
The antineoplastic agent 6-mercaptopurine (6-MP) produces a 50% remission
rate for acute childhood leukemias. Only tumors that convert the drug to its
nucleotide (a active form) by a hypoxanthineguanine
phosphoribosyltransferase(HPRT,次黄嘌呤鸟嘌呤磷酸核糖基转移酶)
SH
O
N
N
N
H
6-mercaptopurine
N
=O PO
3
HO
O
O
O P O P O
O
O
SH
N
OH
5-phosphoribosylpyrophosphate
N
N O N
=O PO
3
OH
HO
6-mercaptopurine nucleotide
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6) Decarboxylation Activation
The obvious treatment for Parkinson’s disease would be to give high
doses of dopamine , but this does not work because dopamine does not
cross the blood–brain barrier. However, there is an active transport system
for L-amino acids; consequently, L-dopa (levodopa) is transported into the
brain where it is decarboxylated by aromatic L-amino acid decarboxylase
(芳香族L-氨基酸脱羧酶）(also called dopa decarboxylase ) to
dopamine .
HO
HO
NH2
H R
levodopa (R=COOH)
Dopamine (R=H)
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Selective delivery of dopamine to the kidneys to attain renal vasodilation
OH
COO
H
N
H3N
O
OH
L-γ-glutamyl
transpeptidase
OH
H3N
COO
OH
COO
Glu
L-aromatic amino
acid decarboxylase
OH
H3N
There is a high concentration of L-γ –glutamyltranspeptidase in kidney cells.
L-amino acid decarboxylase, which also is abundant in kidneys.
This is an example of a site-selective carrier-linked prodrug of a bioprecursor
prodrug for dopamine.
OH
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本章重点内容:
1. 前药的概念：前药是指一类体外无生物学活性、在体内经生物代谢转化后成为
活性药物的化合物。
2. 前药的分类:前药可分为载体连接型前药和生物前体型前药。载体连接型前药
是指一类活性药物与可酶降解的载体以酯、酰胺键相连形成的一类化合物，它又
可分为二元、三元及协同前药。生物前体型前药是指一类能经酶代谢修饰或代谢
转化为活性物质的化合物。
3. 载体前药的设计目的及应用举例:1)改善药物在水中的溶解度；2)改善药物的
体内吸收与分布；3)提高药物的作用部位特异性；4)提高药物代谢稳定性；5)延
长药物作用时间；6)降低药物毒性；7)消除药物的不良气味；8)便于剂型设计。
4. 生物前体性前药的活化及应用举例：1) 质子活化；2) 消除活化；3) 氧化活
化；4) 还原活化；5) 核苷化活化；6) 脱羧活化。