Chapter 5 prodrugs

1. Chapter 5prodrugs

2. 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. Prodrugsand 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.

3. 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

4. 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.

5. 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 directlyor by a linker (also be called twin drug ,孪药).

6. 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.

7. 5.4Carrier-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 itsdosage form.

8. 1） Carrier-Linked Bipartate Prodrugs ① 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

9. 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）

10. 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）

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

12. 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 .

13. 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.

14. 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)

15. 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)

16. 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

17. 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

18. 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.

19. 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).

20. 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.

21. 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 .

22. 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.

23. 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) 克拉维酸 青霉烷砜酸 β-lactamase inhibitor Sultamicillin(舒他西林)

24. ②Aspirin + Paracetamol Benorilate ③Ranitidine Bismuth Citrate,RBC H2- receptor antagonists gastric mucosa protective agent Helicobacter pylori (HP) inhibitor

25. 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.

26. 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

27. 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.

28. 3) Oxidative Activation cyclophosphamide is a prodrug requiring an oxidative mechanism. The activation mechanism is believed to be that shown in Figure in normal cells in normal cells

29. 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 thanin the guinea pig ulcerative colitis model. 柳氮磺吡啶 polymeric drug delivery system

30. 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.

31. 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)

32. 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)

33. Selective delivery of dopamine to the kidneys to attain renal vasodilation L-γ-glutamyl transpeptidase L-aromatic amino acid decarboxylase 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.

34. 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。