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The Organic Chemistry of Drug Design and Drug Action

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1 The Organic Chemistry of Drug Design and Drug Action
Chapter 9 Prodrugs and Drug Delivery Systems

2 Prodrugs and Drug Delivery Systems
Prodrug - 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 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

3 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 and ability to reach site of action 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

4 Utility of Prodrugs (cont’d)
4. Instability - to prevent rapid metabolism; avoid first-pass effect 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

5 Types of Prodrugs Drug 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

6 Protecting Group Analogy for the Concept of Prodrugs
analogous to carrier-linked analogous to bioprecursor Scheme 9.1 Protecting group analogy for a prodrug Keep in mind that a prodrug whose design is based on rat metabolism may not be effective in humans.

7 Mechanisms of Prodrug Activation Carrier-Linked Prodrugs
Most common activation reaction is hydrolysis.

8 Ideal Drug Carriers 1. Protect the drug until it reaches the site of action 2. Localize the drug at the site of action 3. Allow for release of drug 4. Minimize host toxicity 5. Are biodegradable, inert, and nonimmunogenic 6. Are easily prepared and inexpensive 7. Are stable in the dosage form

9 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 lipophilicity ester stability can be controlled by appropriate electronic and steric manipulations

10 Prodrugs for Alcohol-Containing Drugs
Ester analogs as prodrugs can affect lipophilicity or hydrophilicity

11 To accelerate the hydrolysis rate:
attach an electron-withdrawing group if a base hydrolysis mechanism is important attach an electron-donating group if an acid hydrolysis mechanism is important To slow down the hydrolysis rate: make sterically-hindered esters make long-chain fatty acid esters

12 Hydrolysis of amino acid esters of Brivanib

13 Another Approach to Accelerate Hydrolysis Intramolecular hydrolysis of succinate esters
Scheme 9.2 Intramolecular catalysis of succinate esters

14 Enolic hydroxyl groups can be esterified as well.
antirheumatic agent

15 Carboxylic Acid-Containing Groups Esterify as with alcohols

16 Maintaining Water Solubility of Carboxylate Prodrugs
Can vary pKa by appropriate choice of R and R

17 Prodrugs for Phosphate- or Phosphonate-Containing Drugs

18 Amine Prodrugs Amides are commonly not used because of stability
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)

19 N-Mannich base (R = CH2NHCOPh) has a log D7
N-Mannich base (R = CH2NHCOPh) has a log D7.4 two units greater than the parent compound.

20 Another approach to lower pKa of amines and make more lipophilic.
Imine (Schiff base) prodrug hydrolyze imine and amide to GABA inside brain anticonvulsant

21 Acylation of an amidine to make a prodrug
Thrombin inhibitor anticoagulant

22 A Reductive Carrier-Linked Prodrug Approach
Scheme 9.3 Bioreductively activated carrier-linked prodrug

23 Prodrugs of Sulfonamides
A water soluble prodrug of the anti-inflammatory drug valdecoxib (9.13) has been made (9.14).

24 Prodrug Analogs of Carbonyl Compounds
imines oximes ketals Acetals or ketals can be made for rapid hydrolysis in the acidic medium of the GI tract.

25 Examples of Carrier-Linked Bipartate Prodrugs

26 Prodrug Stability Properties
Choice of hydrolytic prodrug group: The group 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.

27 Prodrug for Increased Water Solubility
Prodrug forms for aqueous injection or opthalmic use corticosteroid poor water solubility

28 To avoid formulation of etoposide with detergent, PEG, and EtOH (used to increase water solubility), it has been converted to the phosphate prodrug.

29 Prodrugs of benzocaine with amino acids
R = NH2-CH(R)-CO

30 Prodrug for Improved Absorption Through Skin
corticosteroids - inflammation, allergic, pruritic skin conditions

31 Better absorption into cornea for the treatment of glaucoma
The cornea has significant esterase activity

32 Prodrug for Site Specificity
Bowel sterilant (administer rectally) Prodrug R = Ac (administered orally) Hydrolyzed in the intestines

33 Prodrug for Site Specificity
The 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 (9.21, R = linolenoyl) containing one GABA ester and one vigabatrin ester was 300 times more potent in vivo than vigabatrin.

34 PHOSPHATE Prodrug for liver ACTIVITY
Scheme 9.4 Liver metabolism of drugs containing phosphate and phosphonate moieties

35 Antiviral PRODRUGS

36 Site Specificity Using Enzymes at the Site of Action
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.

37 Enzyme-Prodrug Therapies
For selective activation of prodrugs in tumor cells 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

38 Criteria for Success with Enzyme-Prodrug Therapies
The prodrug-activating enzyme is either nonhuman or a human protein expressed poorly 2. The prodrug-activating enzyme must have high catalytic 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 cytotoxicity 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

39 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 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.

40 ADEPT Advantages: 1. Increased selectivity for targeted cell
2. Each enzyme molecule converts many prodrug molecules 3. The released drug is at the site of action 4. Concentrates the drug at the site of action 5. Demonstrated to be effective at the clinical level Disadvantages: 1. Immunogenicity and rejection of antibody-enzyme conjugate 2. Complexity of the two-phase system and i.v. administration 3. Potential for leakback of the active drug

41 An example is carboxypeptidase G2 or alkaline phosphatase linked to an antibody to activate a nitrogen mustard prodrug. Scheme 9.5 Nitrogen mustard activation by carboxypeptidase G2 for use with ADEPT Humanization of antibodies minimizes immunogenicity. Note the prodrug-activating enzyme is a bacterial enzyme.

42 Antibody-Directed Abzyme Prodrug Therapy (ADAPT)
Instead of using a prodrug-activating enzyme, a humanized prodrug-activating catalytic antibody (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 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.

43 Abzyme 38C2 Activation of a Doxorubicin Prodrug
Scheme 9.6 Catalytic antibody 38C2 activation of a doxorubicin prodrug by tandem retro-aldol/retro-Michael reactions for use with ADAPT

44 Gene-Directed Enzyme Prodrug Therapy (GDEPT) Also known as suicide gene therapy
A gene encoding the prodrug-activating enzyme is expressed in target cancer cells under the control of tumor-selective promoters or by viral transfection. These cells activate the prodrug as in ADEPT. Scheme 9.7 Nitroreductase activation of a prodrug for use with GDEPT

45 Prodrug for Stability protection from first-pass effect
Oral administration has lower bioavailability than i.v. injection. antihypertension plasma levels 8 times that with propranolol

R = Anthranilyl or acetylsalicyl

47 Prodrugs for Slow and Prolonged Release
1. 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 slowly Intramuscular injection is used also

48 Time-release antipsychotics
Sedative/tranquilizer/antipsychotic slow release inject i.m. Antipsychotic activity for about 1 month

49 Time-release antipsychotics
Activity about 1 month

50 A time-release anti-inflammatory drug
t1/2 about 9 h

51 Prodrugs to Minimize Toxicity
Many of the prodrugs just discussed also have lower toxicity. For example, epinephrine (for glaucoma) has ocular and systemic side effects not found in dipivaloylepinephrine. Esters are prodrugs of aspirin

52 Prodrug to Increase Patient Acceptance
The antibacterial drug clindamycin (9.39) is bitter and not well tolerated by children. Clindamycin palmitate is not bitter. Either not soluble in saliva or does not bind to the bitter taste receptor or both.

53 Another bitter drug with a tasteless prodrug

54 Prodrug to Eliminate Formulation Problems
Formaldehyde is a gas with a pungent odor that is used as a disinfectant. Too toxic for direct use. 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.

55 A prodrug for release of acetic acid

56 Areas of Improvement for Prodrugs
site specificity protection of drug from biodegradation minimization of side effects

57 Macromolecular Drug Delivery
To address these shortcomings, macromolecular drug delivery systems have been developed. 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.

58 Disadvantages of Macromolecular Delivery Systems
Macromolecules may not be well absorbed Alternative means of administration may be needed (injection) Immunogenicity problems

59 Macromolecular Drug Carriers
Synthetic polymers Aspirin linked to poly(vinyl alcohol) has about the same potency as aspirin, but less toxic.

60 A prodrug for ibuprofen
9.44 shows a longer half life and longer anti-inflammatory activity

61 Steric Hindrance by Polymer Carrier
poly(methacrylate) to enhance water solubility testosterone No androgenic effect Polymer backbone may be sterically hindering the release of the testosterone.

62 A spacer arm was added, and it was as effective as testosterone.
to enhance water solubility

63 Poly(-Amino Acid) Carriers
poly(L-glutamine) spacer norethindrone - contraceptive Slow release over nine months in rats

64 Poly(-Amino Acid) Carriers
Methotrexate attached to poly(L-lysine) showed increased uptake and overcame resistance

65 General Site-Specific Macromolecular Drug Delivery System
either hydrophilic or hydrophobic for site specificity

66 Site-Specific Delivery of a Nitrogen Mustard
poly(L-Glu) spacer arm water-solubilizing antibody from rabbit antiserum 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).

67 Tumor Cell Selectivity
Drug attached to albumin (R = albumin) Tumor cells take up proteins rapidly. Proteins broken down inside cells, releasing the drug. Shown to inhibit growth of Ectomelia virus in mouse liver, whereas free inhibitor did not. antitumor

68 Antibody-Targeted Chemotherapy
calicheamicin, except as disulfide instead of trisulfide humanized spacer Scheme 9.8 Antibody-targeted chemotherapy, a prodrug for calicheamicin Withdrawn due to release of calicheamicin nonenzymatically. Exhibits no immune response.

69 Antibody-Targeted Chemotherapy
Figure 9.1 (A) Brentuximab vedotin, the first antibody-drug conjugate with a more stable linker; (B) Trastuzumab emtansine, the second antobody-drug conjugate approved

70 Tripartate Drugs (Self-immolative Prodrugs)
A bipartate prodrug may be ineffective because the linkage is too labile or too stable. 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 carrier. The linker-drug bond must cleave spontaneously (i.e., be self-immolative) after the carrier-linker bond is broken.

71 Tripartate Prodrugs Scheme 9.9 Tripartite prodrugs

72 Typical Approach Scheme 9.10 Double prodrug concept

73 Tripartate Prodrugs of Ampicillin
Poor oral absorption (40%) Excess antibiotic may destroy important intestinal bacteria used in digestion and for biosynthesis of cofactors. Also, more rapid onset of resistance. antibacterial Various esters made were too stable in humans (although they were hydrolyzed in rodents) - thought the thiazolidine ring sterically hindered the esterase.

74 Tripartate Prodrugs of Ampicillin
Scheme 9.11 Tripartite prodrugs of ampicillin 98-99% absorbed Ampicillin is released in < 15 minutes

75 Reversible Redox Drug Delivery System to the CNS
hydrolysis activated hydrolysis deactivated hydrophilic drug electron-withdrawing; hydrophilic electron-donating, lipophilic carrier Passive diffusion of 8.47 into the brain; active transport of 8.49 out of the brain Scheme 9.12 Redox drug delivery system to cross the blood–brain barrier XH of the drug is NH2, OH, or COOH If oxidation occurs before it gets into the brain, it cannot cross the blood-brain barrier.

76 When the drug is a carboxylic acid, a self-immolative reaction also can be used.
Scheme 9.13 Redox tripartite drug delivery system

77 Example of Tripartate Redox Drug Delivery
-Lactams are too hydrophilic to cross the blood-brain barrier effectively. Scheme 9.14 Redox tripartite drug delivery of β-lactam antibiotics High concentrations of -lactams delivered into brain.

78 Another Tripartate Prodrug for Delivery of Antitumor drug
Permeases are bacterial transport proteins for uptake of peptides. Scheme 9.15 Activation of peptidyl derivatives of 5-fluorouracil Only L,L-dipeptides are active

79 Another Tripartate Prodrug for Delivery of amines
Scheme 9.16 Tripartite macromolecular drug delivery system This has been applied to daunorubicin

80 Mutual Prodrugs A bipartate or tripartate prodrug in which the carrier is a synergistic drug with the drug to which it is linked. Antibacterial ampicillin -lactamase inactivator penicillanic acid sulfone Hydrolysis gives 1:1:1 ampicillin : penicillanic acid sulfone : formaldehyde

81 Ideal Mutual Prodrugs Well absorbed
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

82 Bioprecursor Prodrugs
Carrier-linked prodrugs largely use hydrolytic activation Bioprecursor drugs mostly use oxidative or reductive activation The metabolically-activated alkylating agents discussed in Chapter 6 are actually examples of bioprecursor prodrugs.

83 Protonation Activation Discovery of Omeprazole
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 called the proton pump), which exchanges protons for potassium ions in parietal stomach cells, thereby increasing stomach acidity.

84 Lead Discovery Lead compound found in a random screen.
Liver toxicity observed thought to be because of the thioamide group.

85 Lead Modification Related analogs made, and 9.72 had good antisecretory activity. Modification gave 9.73 with high activity. The sulfoxide (9.74) was more potent, but it blocked iodine uptake into the thyroid.

86 Lead Modification (cont’d)
Modification of 9.74 gave 9.75 having no iodine blockage activity. Picoprazole shown to be an inhibitor of H+,K+-ATPase. SAR of analogs indicated electron-donating groups on the pyridine ring were favorable. Increased inhibition of H+,K+-ATPase. Best analog was omeprazole (9.76).

87 Formation of 9.77 leads to covalent attachment.
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. Scheme 9.17 Mechanism of inactivation of H+,K+-ATPase by omeprazole Formation of 9.77 leads to covalent attachment. Omeprazole also inhibits isozymes of carbonic anhydrase, another mechanism for lowering gastric acid secretion.

88 Other proton pump inhibitors

89 Hydrolytic Activation
Hydrolysis can be a mechanism for bioprecursor prodrug activation, if the product requires additional activation. Scheme 9.18 Conversion of leinamycin into a series of prodrugs antitumor agent prodrugs of leinamycin

90 Hydrolysis of these analogs gives an intermediate that reacts further to the activated form.
this was synthesized and gave 9.85 as well as DNA cleavage increased stability over leinamycin Scheme 9.19 Hydrolytic activation of leinamycin prodrugs

91 Elimination Activation
potent inhibitor of dihydroorotate dehydrogenase rheumatoid arthritis drug Scheme 9.20 Activation of leflunomide to the active drug Inhibition of dihydroorotate dehydrogenase blocks pyrimidine biosynthesis in human T lymphocytes.

92 Oxidative Activation N-Dealkylation
Scheme 9.21 Bioprecursor prodrugs for alprazolam and triazolam

93 O-Dealkylation Analgesic activity of phenacetin is a result of O-dealkylation to acetaminophen.

94 Oxidative Deamination
Neoplastic (cancer) cells have a high concentration of phosphoramidases, so hundreds of phosphamide analogs of nitrogen mustards were made for selective activation in these cells. Cyclophosphamide was very effective, but it required liver homogenates (contains P450) for activation. Therefore oxidation is required, not hydrolysis. Scheme 9.22 Cytochrome P450-catalyzed activation of cyclophosphamide isolated

95 advanced Hodgkin’s disease
N-Oxidation identified advanced Hodgkin’s disease identified Scheme 9.23 Cytochrome P450-catalyzed activation of procarbazine

96 N-Oxidation Pralidoxime chloride is an antidote for nerve poisons.
It reacts with acetylcholinesterase that has been inactivated by organophosphorus toxins.

97 To increase the permeability of pralidoxime into the CNS, the pyridinium ring was reduced (9.103).
oxidation in brain Similar to the reversible redox drug delivery strategy for getting drugs into the brain by attaching them to a dihydronicotinic acid, hydrophobic crosses the blood-brain barrier; oxidation to prevents efflux from brain.

98 Mechanism of Acetylcholinesterase
Scheme 9.24 Acetylcholinesterase-catalyzed hydrolysis of acetylcholine

99 Inactivation of Acetylcholinesterase by Diisopropyl Phosphorofluoridate
affinity labeling agent irreversible inhibition Scheme 9.25 Phosphorylation of acetylcholinesterase by diisopropyl phosphorofluoridate 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.

100 Reactivation of Inactivated Acetylcholinesterase by Pralidoxime
Scheme 9.26 Reactivation of phosphorylated acetylcholinesterase by pralidoxime chloride

101 Temporary inhibition of acetylcholinesterase enhances cholinergic action on skeletal muscle.
covalent, but reversible inhibition Used for the neuromuscular disease myasthenia gravis Scheme 9.27 Carbamylation of acetylcholinesterase by neostigmine

102 Reversible (noncovalent) inhibitors of acetylcholinesterase, such as donepezil and tacrine are used for Alzheimer’s disease. Enhances neurotransmission involved in memory.

103 S-Oxidation S-oxidation of clopidogrel anticoagulant
Scheme 9.28 S-Oxidation of clopidogrel, which initiates its inactivation of P2Y12

104 Aromatic Hydroxylation Cyclohexenones as prodrugs for catechols
oxidation next to sp2 carbonyl Scheme 9.29 Cytochrome P450-catalyzed conversion of a cyclohexenone to a catechol

105 Alkene Epoxidation active anticonvulsant agent

106 Transamination Stimulation of pyruvate dehydrogenase results in a change of myocardial metabolism from fatty acid to glucose utilization. Glucose metabolism requires less O2 consumption. Therefore, utilization of glucose metabolism would be beneficial to patients with ischemic heart disease (arterial blood flow blocked; less O2 available).

107 Arylglyoxylic acids (8.104) stimulate pyruvate dehydrogenase, but have a short duration of action.
Oxfenicine (8.105, R = OH) is actively transported and is transaminated (a PLP aminotransferase) in the heart to (R = OH).

108 Reductive Activation Azo Reduction
Anaerobic cleavage by bacteria in lower bowel ulcerative colitis For inflammatory bowel disease Causes side effects Scheme 9.30 Reductive activation of sulfasalazine

109 To prevent side effect by sulfapyridine a macromolecular delivery system was developed.
poly(vinylamine) Not absorbed or metabolized in small intestine. spacer Released by reduction at the disease site. Sulfapyridine is not released (still attached to polymer). More potent than sulfasalazine.

110 Azido Reduction antiviral drug Vidarabine is rapidly deaminated by adenosine deaminase , R = N3 is not a substrate for adenosine deaminase and also can cross the blood-brain barrier for brain infections.

111 Sulfoxide Reduction anti-arthritis Sulindac is inactive in vitro; the sulfide is active in vitro and in vivo.

112 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 solubility.

113 Disulfide Reduction To increase the lipophilicity of thiamin for absorption into the CNS. nonenzymatic poorly absorbed into CNS Scheme 9.31 Conversion of thiamin tetrahydrofurfuryl disulfide to thiamin

114 Therapeutic index of 9.128 is 12 times higher than 9.127 in mice.
To diminish toxicity of primaquine and target it for cells with the malaria parasite, a macromolecular drug delivery system was designed. antimalarial, toxic Intracellular thiol much higher than in blood; selective reduction inside the cell primaquine for improved uptake in liver Therapeutic index of is 12 times higher than in mice.

115 Nitro Reduction Scheme 9.32 Reductive activation of ronidazole

116 Nitro reduction activation
Scheme 9.33 Phosphoramidite-based prodrug for intracellular delivery of nucleotides

117 Nucleotide Activation
Anti-leukemia drug Inhibits several enzymes in the purine nucleotide biosynthesis pathway. Scheme 9.34 Nucleotide activation of 6-mercaptopurine

118 Phosphorylation Activation
antiviral 2-deoxyguanosine Resembles structure of 2-deoxyguanosine viral thymidine kinase Uninfected cells do not phosphorylate acyclovir (selective toxicity) R = PO3= viral guanylate kinase R = P2O63- viral phosphoglycerate kinase R = P3O94-

119 Acyclovir triphosphate is a substrate for viral -DNA polymerase but not for normal -DNA polymerase
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

120 Resistance to Acyclovir
Modification of thymidine kinase Change in substrate specificity for thymidine kinase Altered viral -DNA polymerase

121 Only 15-20% of acyclovir is absorbed
Therefore, prodrugs have been designed to increase oral absorption. Hydrolyzes here Prodrug for a prodrug adenosine deaminase acyclovir

122 This prodrug is 18 times more water soluble than acyclovir.
Hydroxylates here xanthine oxidase acyclovir This prodrug is 18 times more water soluble than acyclovir.

123 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.

124 An analog of acyclovir whose structure is even closer to that of 2-deoxyguanosine is ganciclovir.
More potent than acyclovir against human cytomegalovirus.

125 Two carbon isosteres of ganciclovir are available.
C in place of O C in place of O Better oral absorption than penciclovir Converted to penciclovir rapidly

126 Sulfation Activation Activity of minoxidil requires sulfotransferase-catalyzed sulfation to minoxidil sulfate. hair growth Inhibitors of the sulfotransferase inhibit the activity of minoxidil, but not minoxidil sulfate.

127 Decarboxylation Activation
An imbalance in the inhibitory neurotransmitter dopamine and the excitatory neurotransmitter 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).

128 Does not reverse the disease, only slows progression.
After crossing blood-brain barrier L-aromatic amino acid decarboxylase (PLP) dopamine (R = H) Does not reverse the disease, only slows progression.

129 Combination Therapy Monoamine oxidase B (MAO B) degrades dopamine 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.

130 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. (used in U.S.) (used in Europe and Canada) Selectively inhibits peripheral L-amino acid decarboxylase. The dose of L-dopa can be reduced by 75%.

131 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 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 (R = H), a selective MAO A mechanism-based inactivator. Carbidopa protects (R = COOH) from decarboxylation outside of the brain.

132 Selective Delivery of Dopamine to Kidneys
Dopamine increases renal blood flow. Prodrugs were designed for selective renal vasodilation. L-dopa L--glutamyl-L-dopa Dopamine accumulates in the kidneys because of high concentrations of L--glutamyltranspeptidase and L-aromatic amino acid decarboxylase there. Example of a carrier-linked prodrug of a bioprecursor prodrug for dopamine. Scheme 9.35 Metabolic activation of l-γ-glutamyl-l-dopa to dopamine

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