drug design metabolism 3

8/3/2019 Drug Design Metabolism 3

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Regulation of drug stability

increase the in vivo stability of an active compound and prolong itsaction or can automatically limit the duration of the drug and preventpotential toxicity.

Replacement of a "vulnerable moiety" such as a methyl group byless readily oxidized chlorine was used to transform the short-actingtolbutamide, an oral antidiabetic, into the long-acting chlorpropamide

with half-life six fold greater than its parent.

NH2 C O CH 2CH 2N

O

NH2 C NHCH 2CH 2N

C2H5O

Procaine Procainamide

C2H5

C2H5 C2H5

These modifications can result in a change of pharmacological activity.The replacement of the ester group in the local anaesthetic procaine by anamide group produced procainamide which acts as an antiarrythmic.

Tolbutamide Chlorpropamide

CH3 SNH

O

ONH

O

C4H9

Cl SNH

O

ONH

O

C4H9


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Prodrugs Prodrugs are inactive compound that yield an active compound on metabolism in the body.

They are broadly classified in two groups: carrier prodrugs, bioprecursor.

1- The carrier-linked prodrugs: The drugs that have been attached through a metabolically labile linkage to another molecule

called pro-moiety, this pro-moiety may impart some desirable property to the drug such asincreased lipid or water solubility and may itself have no role in activity.

The pro-moeity should be: inactive or less active than the parent drug, Rapid, easily and completely removed after it has served its function non-toxic

drug ___________Carrier drug ______linking str______Carrier

Bipartate (Tolmetine________glycine) tripartate (Ampicillin__OCHOCH3_____COC2H5)

2- The bioprecursor prodrugs:Inactive drugs in vitro and they are converted to its active form in vivo bychemical metabolic pathway.Contain the embryo of the active drug.


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1- carrier linked prodrug

Tripartate carrier-linked prodrug: A good example of a carrier prodrug is bacampicillin,it is one of the prodrugs of ampicillin. 40% of an orally adminstered dose of ampicillinis absorbed, however 98-99% of the prodrug is absorbed, so we can decrease the

therapeutic dose used so decrease risk of toxic response, Carbon dioxide , ethanoland acetaldehyde are natural metabolites

N

S CH3

CH3

O

O

CH3

OOC 2H5

O

HN

O

R

O

Bacampicillin

N

S CH3

CH3

O

OCH

CH3

OH

HN

O

R

O

CO 2 C2H5OH

N

S CH3

CH3

O

OH

HN

O

R

O

CH3CHO

Ampicillin

R=NH2

CO

+ +

+


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The design of prodrug System for specific Purposes

1- Improve absorption:

Introduction of lipophilic groups as in Dipivefrin HCl which is aprodrug of epinephrine in which the catechol hydroxyl groups havebeen utilized in the formation of an ester linkage with pivalic acid.The previous agent is used in treatment of glaucoma. Increasing itslipophilicity relative to epinephrine allows the agent to move acrossthe membrane of the eye easily when applied thus achievinghigher intraocular concentrations.

Pivalic acid here is the promoeity, hydrolysis of the ester after ithas crossed the membrane barriers of the eye is then achieved togive the active form "epinephrine".

OH

(CH 3)3CCOO

NH 2(CH 3)3CCOO

CH 3

Cl

OH

OH

NH2

OH

CH 3

Cl+

+

epinephrin

+ Pivalic acidEsterase

Dipivaloyl

good absorption through cornea


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2- Increasing solubility: By introduction of a hydrophilic moiety 1- To improve solubility of chloramphenicol for its parental use by usingaqueous solution of chloramphenical succinate or phosphate as water solubleesters & salt can be adminstered water soluble IV injection.

2- Prednisolone (steroid hormone) water soluble injectable form Byformation of Phosphate, Succinate Or Sulphate ester salt

CH 2-OH

OH

Prednisone Prednisone Sodium Succinateester

Water soluble

R-gp.

HO

O

O CH 2-O-C-CH 2CH 2COO _ Na +

OHHO

O

O

O

CH2-O C

O

C

O

O

O -Na +

O -Na +

P

Chloramphenicol Succinate

ester

Salt

ester + ionizable salt

Chloramphenicol Phosphate

Na + -O

CH2-O

EX. : Chloramphenicol succinate

EX. : Prednisone succinate


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3- Improving patient acceptance

Taste improvement is quite an important aspect of drug

modification especially in pediatric medicine. The extremelybitter taste of some antibiotics such as clindamycin orchloramphenicol can be masked successfully by preparingpamitate ester of these drugs.

The bitterness of the drug results when the drug begins todissolve in the mouth and then is capable of interacting withreceptors.

A prodrug with reduced water solubility doesn't dissolve to anyappreciable extent in the mouth and therefore doesn't interactwith taste receptors.

OCH

HOH

HH

OH

OCO(CH 2)14CH 3

H

CONH

SCH 3

H

CHCl

CH 3N H

HCH

2CH

2CH

3

CH 3

Clindamycin- 2-palmitate

tasteless


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4- To Prolong Duration of Drug Action ( Prolonged release:)

Prodrugs may be used to prolong the duration of action by providinga slow release mechanism for the drug by slow hyrolysis of amide orester-linked fatty acid carriers.

Steroid hormones palmitates and pamoates and antimalarial estersor insoluble salts (e.g. cycloguanil pamoate) can deliver the activedrugs for a long time.

N N

H2N

CH 3

CH 3

ClNH 2

CH 2OH

COO

COO

OH

Cycloguanil pamoate

EX.1 : Cycloguanil pamoateAs I.M oil injection last for 1 month as antimalarial

EX. 2: Tolmetine

As antiinflamatory drug its duration is 1 hr but its linking with glycine carrier Increase its duration to 9 hrs.


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EX.3 : Haloperidol & Fluphenazine decanoate:As I.M oil injection last for 1 month as antipsychotic

F

NOR

Cl

O

Haloperidol : R = H

N

S

CH2

CF 3

CH2 CH2 N N CH 2 CH2 OR

Fluphenazine: R = H

R = C

O

(CH 2 )8 -CH 3

Decanoate Ester


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5- To decrease Toxicity ( side effect ) :

the drug is administered in a nontoxic, inactive form & then slowly

converted to the active form to prevent gastric irritation.

EX. Diglyceride ester of NAPROFEN (NSAID)

CH2-CH-COOHMeO

CH3

COO

CH2O-CO(CH 2)11 CH3

CH

CH2O-CO(CH 2)11 CH3

Naproxen (Anti-inflammatory)

With Gastric irritation side effect

Diglycerides Ester


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Naltrexone : ( R = H)

O

N

HO

ORO

CO

H2N

R =

C

AcO

R =O

Anthranilate :

Acetyl Salicylate:

It undergoes 1 st pass metabolism PRODRUGS of 45-& 28-fold more effective resp.

for treatment of opoid addiction

6- To avoid drug instability: To avoid first pass metabolism.

EX. : Naltrexone anthranilate or acetyl salicylate esters


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NH

O

O C

O

CH3

OC

O

H3C

Prodrug ester for oxyphenisatincan be taken orally

estrase in intestine

NH

O

OH

HO

Active oxyphenisatin"bowel sterilant"

Ex.2 : Diethyl stilbosterol Diphosphate Fosfosterol

Its more selective in treatment of prostaticCancer than DES, as the prostatic cancer tissuecontains high conc. of Phosphatase enzyme ,where DES phosphate is activated only at thesite of tumor.

P

P

O

OH

OH

O

OHHO

O

O

7- Site specificity (DRUG TARGETING )

The acetylated form can be taken orally & activated onlyin the intestine but Oxyphenisatin can be taken rectally.

Ex.1 : Oxyphenisatin :


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Ex.3: Progabide : It is a prodrug for g amino butyric acid (GABA)

-GABA itself is too hydrophilic and can not cross BBB-So prodrug increases lipophilicity to cross BBB, once inside the brain it ishydrolyzed to GABA.

N

OH

Cl

FN

OHO

OH

Cl

F

Schiff's base linkage

active part

Progabide

in BrainH2N

O

OH

GABA


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N

Me

C X- Drug

PRODRUG with carrier system1,4-dihydropyridine- 3-carboxylic acid

Lipophilic

OBBB

Metabolism

(Oxidase)N

Me

C X- Drug

O

Quaternary ionic form

(locked in brain)

N

Me

C X- Drug

O

+

+

Trigonelline( nontoxic)

Hydrolysis

N

Me

+

COOHActive drug

Ex.4 : Brain-specific delivery : by Dihydropyridinepyridinium system

By attaching a reversible redox drug delivery system to the drug

cross BBB& Once inside the brain the carrier is oxidized into a hydrophiliccompound tobe kept in the brain which is slowly hydrolyzed to the drug.


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Ex.2: b -lactam antibiotics : -For treatment of bacterial meningitis. -lactams are hydrophilic can not cross BBB by themselves. Dihydropyridine carrier to -lactams make them able to cross BBB.Tri partate prodrug : (( Double ester with penicillins ))

Linker

Double ester ( Highly lipophilic )

pass BBB( Highly hydrophilic )

Locked in brain

BrainOxidation

Carrier

N

S

O

CH3

CH3

C

O

O X C

O

N

CH3

HNC

O

R

N

S CH3

CH3

C

O

OX

CO

N

CH3

B B B

BBB Carrier System

(Lipophilic)

In vivo Cleavage{ esterase}

GABA

N

Me

C

O

NHCH 2-CH2-CH 2-COO-C 6H11

GABA

( can not penetrate BBB)

H3N CH 2-CH 2-CH 2-COO -

Ex.1: GABA


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+

Oxidizedtransport form

Prodrug

Trifluridine

this hydrophilic salt can't cross the BBB

thus remains confined to the CNS &slowly hydrolyzeto trifluridine

Reduced transport form

N

NO

CF3

O

O

H

HO-H 2C

O C

O N

CH 3

N

NO

CF 3

O

O

H

HO-H 2C

OH

N

NO

CF 3

O

O

H

H2COCO

C(CH 3)3O C

ON

CH 3

The cytostatic trifluridine to the CNS by the use of N-methyldihydropyridinederivative Trifluridine which is too polar to cross the BBB in an unaltered forminhibit thymidylate synthase in cancer cells, inhibit DNA synthesis andproduces death of the cell.Attachment of the dihydropyridine ester allows passage of the compoundsinto the CNS, where it is easily oxidized by the oxidases found in the brain tothe quaternary pyridine cation which is highly polar & thus trapped in thebrain. The drug is then released from the pyridine cation by a secondmetabolic or chemical event.The pyridinium-trifluridine is a soft prodrug from which the active trifluridine isslowly liberated.

Ex.3: Trifluridine


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Bio-Precursor Prodrugs: CompoundInvivo

Metabolic reactionActive CompoundInactive

Metabolic activation of bioprecursors:

1) Oxidative activation

1. O Dealkylations:

Phenacetin(inactive)

OH

NHCOCH 3

in-vivo

METABOLISM

Acetaminophen ( Paracetamol )

very active analgesic & antipyretic

NHCOCH 3

OEt

2. Oxidation with cytochrome p 450:

PN

ON

Cl

OCl liver

CYP- 450

PNH2

OHN

Cl

OCl

Cyclophosphamide (inactive) Phosphoramidate mustard (antineoplastic)


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2) Reductive activation: -

1. Azoreduction:

H2N N N

NH2

S

O

O

NH2

Prontosil( inactive )

Azoreductase H2N S

O

O

NH2

Sulfanilamide

( Active )

CH3

F

O

CH3

F

in-vivo

Sulindac ( inactive )

Reductive METABOLISM

Sulindac sulfide ( active )

CH2-COOH

CH3-S

CH2-COOH

MeS

2. Sulfoxide reduction:


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3) Nucleotide Activation:

N

N N

N

SH

H

6-MP

OOPO

O

O

HO OHO P

OO

O

PO

O

O

N

N N

N

SH

O

OHOH

OP

O

O

O

6-Mercapto inosinate(Active Antitumor agent )

(Inactive prodrug )

5-phosphoribosyl pyrophosphate

Hypoxanthine-guanine phosphoribosyl transferase

COOH

NH2HO

HO

L-Dopa

DOPA DecarboxylaseNH2HO

HO

Dopamine

( Active)(Prodrug for dopamine) Cross BBB

*

4) Decarboxylative activation:


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A carrier-linked prodrug is a prodrug that contains a temporary linkage of agiven active substance with a transient carrier group that produces improvedphysicochemical or pharmacokinetic properties and that can be easily removedin vivo, usually by a hydrolytic cleavage

which contains an active drug linked to a carrier group by an easily breakablechemical bond. This complex shows improved physicochemical orpharmacokinetic properties and can be cleaved in vivo usually by hydrolyticcleavage to yield the active drug. Carrier-linked prodrugs are divided intobipartite prodrugs with one carrier (group) attached to the drug, tripartite with acarrier group attached via a linker to the drug and mutual prodrugs with twodrugs linked together one of which acts as a carrier for the other and visa versa.Mutual prodrugs can be bipartite or tripartite. For example, sultamacillin is atripartite mutual drug and an ester of ampicillin and sulbactam (a penicillanicacid sulphone). Ampicillin is an antibiotic and sulbactam is a -lactamaseinhibitor which inhibits the metabolism of ampicillin by -lactamases.

Bioprecursor: prodrugs which are chemically modified in the body themodification of which generates a new compound which is either active or whichcan be transformed metabolically or chemically to form an active compound.

drug design metabolism 3

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