Chapter 5 prodrugs

Chapter 5prodrugs

Shanghai Jiao Tong University

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.

前药


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


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.

D + C DC D + Cmodification metabolism

active drug carrier prodrug active drug carrier


tripartate prodrug （三元前药） : a carrier is connected to drug with a linker

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 ).

D + Ln + C D-Ln-C D- Ln + Cmodification metabolism

active drug carrier prodrug

active drug

carrierlinker inactive

D - L + L1 + L2 + L3 ......metabolism

D + Llinker

D1(P1) + D2(P2) D1 + D2

linking metabolism

active drug or pharmacophore

prodrug

D1(P1) - D2(P2)

active drug

D1(P1) + L + D2(P2)

linkerD1(P1) - L - D2(P2)

linkingD1 + D2 + Lmetabolism


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

Daactive drug


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.


1 ） Carrier-Linked Bipartate Prodrugs① Prodrugs for Increased Water Solubility

prednisolone (R = R’ = H)( 泼尼松龙）

methylprednisolone (R = CH3, R’ = H)

methylprednisolone sodium succinate (R = CH3, R’ = COCH2CH2CO2Na)

prednisolone phosphate (R = H, R’ = PO3Na2)

poorly water-soluble

water-soluble

O

Me

HOMe

R

OH

O

R'O


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)

fluocinolone acetonide (R = H) （肤轻松）

fluocinonide (R = COCH3) （醋酸肤轻松）

O

Me

HOMe

F

O

RO

F

O

OMe

Me


A prodrug for the antiglaucoma （抗青光眼） drug epinephrine （地匹福林）

dipivefrin (R = Me3CCO)

epinephrine (R = H) （肾上腺素）

RO

ROOH

NHCH3


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.

Progabide

progabide is an effective lipophilic analog of GABA that crosses the blood–brain barrier, releases GABA inside the brain, and shows anticonvulsant activity.

H2N COOH

GABA

NF

OHO

NH2

Cl


b. Antibody-directed enzyme prodrug therapy(ADEPT)

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 .

NII

O

O

HN CO2H

CO2H

NII

OH

L-Glu CO2

electron-donating:activates nitrogen mustard

electron-withdrawing:deactivate nitrogen mustard

carboxypeptidase G2


④ Prodrugs for Stability

propanolol (R = R’ = H)（普奈洛尔）

O-glucuronide ( R=H,OR’=glucuronide), metabolite

p-hydroxypropranolol( R =OH,R’=H), metabolite

O-glucuronide(R=OH,OR’=glucuronide)

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.

O

OR'

NHCH(CH3)2

R


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.

haloperidol (R=H) （氟哌啶醇）

haloperidol decanoate (R = CO(CH2)8CH3)

IO

NOR

Cl


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

aspirin (R = H)

N,N-disubstituted 2-hydroxyacetamides

( R=CH2CONR1R2)O

OR

O

CH3

O


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.

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

N

CH3H

O

HN Cl

H OHO OH

OR

SCH3


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.

Methenamine

NN

N

N


2) Tripartate ProdrugsBipartate 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.


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).

The double ester

Drug X CH2

O

CO

Resterase

Drug XH2C O RCOOH

f ast

Drug X CH2O


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.

N

S

OO

O

R

R'

O

O

NH

O

Ph

NH2esterase

N

S

OO

OH

R

O

NH

O

Ph

NH2 R'COOH

EtOH + CO2

when:R'=OH

8.46

R H

Obacampicillin(R=CH3,R'=OEt)pivampicillin(R=H,R'=t-Bu)

8.45


②The prodrug to cross the blood–brainbarrier passively

(a dihydropyridine delivery system)

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 .

N

CH3

X

O

Drug

cross blood-brain barrier

N

CH3

X

O

Drug

N

CH3

X

O

Drugenzyme

oxidation

enzymehydrolysis

N

HOOC

CH3

XHDrug


A tripartate example of this approach is the brain delivery of β-lactam antibiotics for the possible treatment of bacterial meningitis(脑膜炎） .

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.

esterase

N

Me

O

O

OO

S

N

HNR

OO

8.51

oxidation

N

Me

O

O

OO

S

N

HNR

OO

esterase

OOO

S

N

HNR

OO

-CH2O

N

Me

O

O

OO

S

N

HNR

OO


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.

β-lactamase inhibitor

Sultamicillin(舒他西林 )

HO

NH2

NHO

N

S

COOHO

amoxicillin

N

O

COOHO

OH

potassium clavulanate

N

S

COORO

O O

penicillanic acid sulf one(R=H)

N

S

O

NH

NH2

Ph

O

O

O O

O

N

S

O

OO

克拉维酸青霉烷砜酸

①Sultamicillin( 舒他西林 )


②Aspirin + Paracetamol Benorilate

③Ranitidine Bismuth Citrate,RBC

H2- receptor antagonists gastric mucosa protective agent

Helicobacter pylori (HP) inhibitor

COO

OCOCH3

NHCOCH3

O(H3C)2NH2CS

NH

NHCH3

CHNO2

HO

O

O

C

O

O

O

O

Bi+3


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.


1) Proton Activation:

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 proton-initiated transformation to active form, which reacts covalently with a cysteine residue of H+,K+-ATPase

N

OCH3

CH3H3C

SHN

N

OCH3

O

H+

N

OCH3

CH3H3C

SHNN

OCH3

HO

N

OCH3

CH3H3C

SHNN

OCH3

OH

N

OCH3

CH3H3C

NS

N

OCH3

-SN

OCH3

CH3H3C

NH

S

N

OCH3

S

+ H+H2O


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.

NO

H

CH3

NH

OCF3B:

+BH

CF3

NH

HO CH3

O

CN


3) Oxidative Activation

in normal cellsin normal cells

NH

OP

O

O

NCl

Cl

H2N

OP

O

NCl

Cl

HOOC

NH

OP

O

NCl

Cl

H2N

OP

O

NCl

Cl

P450NH

OP

O

NCl

Cl

HO HO

H

Bcyclophosphamide

O

H

H2N

OP

O

NCl

Cl

spontaneous

orphosphoramidase

HNCl

Cl

NH3HPO42+

cyclophosphamide is a prodrug requiring an oxidative mechanism. The activation mechanism is believed to be that shown in Figure


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.

NNHS

O

O

N N OH

COOH

sulfasalazine

H2N OH

COOH

NNHS

O

O

NH2 N

SO2

N

CO2Na

OH

Na

柳氮磺吡啶

polymeric drug delivery system


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.

N

N N

N

NH2

O

HO

HO

OH

N

N N

N

N3

O

HO

HO

OH

CYP450-catalyzed

reduction

Vidarabine9-(¦Â -D-Arabinofuranosyl)-6-azidopurine


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 )

N

N NH

N

SH

6-mercaptopurine

O

HO OH

OO3PO

P

O

O

O P

O

O

O=

N

N N

N

SH

O

O3PO

HO OH

=5-phosphoribosylpyrophosphate

6-mercaptopurine nucleotide


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 .

levodopa (R=COOH)

Dopamine (R=H)

HO

HO

NH2RH


Selective delivery of dopamine to the kidneys to attain renal vasodilation

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.

L-aromatic amino acid decarboxylase

L-γ-glutamyltranspeptidase

OH

OH

HN

COOO

H3N

COO

Glu

OH

OHH3N

COO

OH

OHH3N


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。

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Chapter 5 prodrugs