Presentation on theme: "The Organic Chemistry of Drug Design and Drug Action"— Presentation transcript:
1 The Organic Chemistry of Drug Design and Drug Action Chapter 9Prodrugs 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 biotransformationIdeally, 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 forma soft drug is active - uses metabolism to promote excretionA pro-soft drug would require metabolism to convert it to a soft drug
3 Utility of Prodrugs1. Aqueous Solubility - to increase water solubility so it can be injected in a small volume2. Absorption and Distribution - to increase lipid solubility to penetrate membranes for better absorption and ability to reach site of action3. 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 effect5. Prolonged Release - to attain a slow, steady release of the drug6. Toxicity - to make less toxic until it reaches the site of action7. Poor Patient Acceptability - to remove an unpleasant taste or odor; gastric irritation8. 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 prodrugA compound that contains an active drug linked to a carrier group that is removed enzymaticallyA. bipartate - comprised of one carrier attached to drugB. tripartate - carrier connected to a linker that is connected to drugC. mutual - two, usually synergistic, drugs attached to each otherII. Bioprecursor prodrugA 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 tocarrier-linkedanalogous tobioprecursorScheme 9.1 Protecting group analogy for a prodrugKeep 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 Carriers1. Protect the drug until it reaches the site of action2. Localize the drug at the site of action3. Allow for release of drug4. Minimize host toxicity5. Are biodegradable, inert, and nonimmunogenic6. Are easily prepared and inexpensive7. 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 esteresterases are ubiquitouscan prepare esters with any degree of hydrophilicity or lipophilicityester 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 importantattach an electron-donating group if an acid hydrolysis mechanism is importantTo slow down the hydrolysis rate:make sterically-hindered estersmake long-chain fatty acid esters
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 effectivepKa 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) prodrughydrolyze imine and amide to GABA inside brainanticonvulsant
21 Acylation of an amidine to make a prodrug Thrombin inhibitoranticoagulant
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 formsfor aqueous injection or opthalmic usecorticosteroidpoor 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
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 cellsTwo steps:1. incorporate a prodrug-activating enzyme into a target tumor cell2. 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 poorly2. The prodrug-activating enzyme must have high catalytic activity3. The prodrug must be a good substrate for the incorporated enzyme and not for other endogenous enzymes4. The prodrug must be able to cross tumor cell membranes5. The prodrug should have low cytotoxicity and the drug high cytotoxicity6. 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 molecules3. The released drug is at the site of action4. Concentrates the drug at the site of action5. Demonstrated to be effective at the clinical levelDisadvantages:1. Immunogenicity and rejection of antibody-enzyme conjugate2. Complexity of the two-phase system and i.v. administration3. 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 ADEPTHumanization 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.antihypertensionplasma levels 8 times that with propranolol
46 Prodrug FOR NALTREXONE R = Anthranilyl or acetylsalicyl
47 Prodrugs for Slow and Prolonged Release 1. To reduce the number and frequency of doses2. To eliminate night time administration3. To minimize patient noncompliance4. To eliminate peaks and valleys of fast release (relieve strain on cells)5. To reduce toxic levels6. To reduce GI side effectsLong-chain fatty acid esters hydrolyze slowlyIntramuscular injection is used also
48 Time-release antipsychotics Sedative/tranquilizer/antipsychoticslow releaseinject 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.
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.
56 Areas of Improvement for Prodrugs site specificityprotection of drug from biodegradationminimization 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 absorbedAlternative means of administration may be needed (injection)Immunogenicity problems
59 Macromolecular Drug Carriers Synthetic polymersAspirin 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 solubilitytestosteroneNo androgenic effectPolymer 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)spacernorethindrone - contraceptiveSlow release over nine months in rats
64 Poly(-Amino Acid) Carriers Methotrexate attached to poly(L-lysine)showed increased uptake and overcameresistance
65 General Site-Specific Macromolecular Drug Delivery System either hydrophilic or hydrophobicfor site specificity
66 Site-Specific Delivery of a Nitrogen Mustard poly(L-Glu)spacer armwater-solubilizingantibody from rabbit antiserum against mouse lymphoma cellsAll 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 trisulfidehumanizedspacerScheme 9.8 Antibody-targeted chemotherapy, a prodrug for calicheamicinWithdrawn 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.
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.antibacterialVarious 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 ampicillin98-99% absorbedAmpicillin is released in < 15 minutes
75 Reversible Redox Drug Delivery System to the CNS hydrolysis activatedhydrolysis deactivatedhydrophilic drugelectron-withdrawing; hydrophilicelectron-donating,lipophilic carrierPassive diffusion of 8.47 into the brain; active transport of 8.49 out of the brainScheme 9.12 Redox drug delivery system to cross the blood–brain barrierXH of the drug is NH2, OH, or COOHIf 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 antibioticsHigh 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-fluorouracilOnly L,L-dipeptides are active
79 Another Tripartate Prodrug for Delivery of amines Scheme 9.16 Tripartite macromolecular drug delivery systemThis has been applied to daunorubicin
80 Mutual ProdrugsA bipartate or tripartate prodrug in which the carrier is a synergistic drug with the drug to which it is linked.Antibacterial ampicillin-lactamase inactivatorpenicillanic acid sulfoneHydrolysis gives 1:1:1 ampicillin : penicillanic acid sulfone : formaldehyde
81 Ideal Mutual Prodrugs Well absorbed Both components are released together and quantitatively after absorptionMaximal effect of the combination of the two drugs occurs at 1:1 ratioDistribution/elimination of components are similar
82 Bioprecursor Prodrugs Carrier-linked prodrugs largely use hydrolytic activationBioprecursor drugs mostly use oxidative or reductive activationThe 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 ModificationRelated 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 omeprazoleFormation of 9.77 leads to covalent attachment.Omeprazole also inhibits isozymes of carbonic anhydrase, another mechanism for lowering gastric acid secretion.
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 prodrugsantitumor agentprodrugs 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 cleavageincreased stability over leinamycinScheme 9.19 Hydrolytic activation of leinamycin prodrugs
91 Elimination Activation potent inhibitor of dihydroorotate dehydrogenaserheumatoid arthritis drugScheme 9.20 Activation of leflunomide to the active drugInhibition 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-DealkylationAnalgesic 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 cyclophosphamideisolated
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 brainSimilar 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 agentirreversible inhibitionScheme 9.25 Phosphorylation of acetylcholinesterase by diisopropyl phosphorofluoridateInactivation 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 inhibitionUsed for the neuromuscular disease myasthenia gravisScheme 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 carbonylScheme 9.29 Cytochrome P450-catalyzed conversion of a cyclohexenone to a catechol
106 TransaminationStimulation 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 bowelulcerative colitisFor inflammatory bowel diseaseCauses side effectsScheme 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.spacerReleased by reduction at the disease site.Sulfapyridine is not released (still attached to polymer).More potent than sulfasalazine.
110 Azido Reductionantiviral drugVidarabine 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 Reductionanti-arthritisSulindac 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 ReductionTo increase the lipophilicity of thiamin for absorption into the CNS.nonenzymaticpoorly absorbed into CNSScheme 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, toxicIntracellular thiol much higher than in blood; selective reduction inside the cellprimaquinefor improveduptake in liverTherapeutic index of is 12 times higher than in mice.
115 Nitro ReductionScheme 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 drugInhibits several enzymes in the purine nucleotide biosynthesis pathway.Scheme 9.34 Nucleotide activation of 6-mercaptopurine
118 Phosphorylation Activation antiviral2-deoxyguanosineResembles structure of 2-deoxyguanosineviral thymidine kinaseUninfected cells do not phosphorylate acyclovir (selective toxicity)R = PO3=viral guanylate kinaseR = P2O63-viral phosphoglycerate kinaseR = 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 kinaseChange in substrate specificity for thymidine kinaseAltered viral -DNA polymerase
121 Only 15-20% of acyclovir is absorbed Therefore, prodrugs have been designed to increase oral absorption.Hydrolyzes hereProdrug for a prodrugadenosine deaminaseacyclovir
122 This prodrug is 18 times more water soluble than acyclovir. Hydroxylates herexanthine oxidaseacyclovirThis 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 OC in place of OBetter oral absorption than penciclovirConverted to penciclovir rapidly
126 Sulfation ActivationActivity of minoxidil requires sulfotransferase-catalyzed sulfation to minoxidil sulfate.hair growthInhibitors 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 barrierL-aromatic amino acid decarboxylase (PLP)dopamine (R = H)Does not reverse the disease, only slows progression.
129 Combination TherapyMonoamine 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-dopaL--glutamyl-L-dopaDopamine 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