Prodrugs Concept & Applications PDF

Prodrugs concept & Applications Lec. 4 Non-prodrugs It is also important to distinguish prodrugs from soft and hard drugs. Hard drugs:- are compounds that are designed to contain the structural characteristics necessary for pharmacological activity bu...

Prodrugs concept & Applications Lec. 4 Non-prodrugs It is also important to distinguish prodrugs from soft and hard drugs. Hard drugs:- are compounds that are designed to contain the structural characteristics necessary for pharmacological activity but in a form that is not susceptible to metabolic or chemical transformation. 1- Increased efficiency by avoiding metabolism. 2- No toxic metabolites are formed. 3- HOWEVER, less readily eliminated due to lack of metabolism..  Soft drugs: - There are two mechanism for the conversion of prodrug to an active drug:-  Types of prodrugs: Various prodrugs for compounds containing different functional groups are listed below: 1. Esters. 2. Prodrug for Amides, Imides and Other Acidic Compounds. 3. Prodrugs for Amines, and. 4. Prodrugs with Carbonyl Groups. 30-Sep-17 22 1 Ester pro drug. If the molecule contains either an alcohol or carboxylic acid functionality an ester prodrug may be easily synthesized. Examples:- Chloramphenicol(antibiotic)  Chloramphenicol when given parentrally by IM inj. it is painful ,since it ppt. at site of injection because of its low water solubility, so when polar functional group like succinate was added lead to increase water solubility and reduce pain.  Activated amides, generally of low-basicity amines, or amides of amino acids are more susceptible to enzymatic cleavage (Table 9.3).  Activated amides, generally of low-basicity amines, or amides of amino acids are more susceptible to enzymatic cleavage (Table 9.3).  Although carbamates in general are too stable, phenyl carbamates (RNHCO2Ph) are rapidly cleaved by plasma enzymes, and, therefore, they can be used as prodrugs.  Activated amides, generally of low-basicity amines, or amides of amino acids are more susceptible to enzymatic cleavage (Table 9.3).  Although carbamates in general are too stable, phenyl carbamates (RNHCO2Ph) are rapidly cleaved by plasma enzymes, and, therefore, they can be used as prodrugs.  N-Mannich bases as a prodrug: The pKa of amines can be lowered by approximately three units by conversion to their N-Mannich bases.   A more common approach has been to use Mannich bases as a prodrug form of the amines.  Mannich bases result from the reaction of two amines with an aldehyde or ketone. Mannich bases as a prodrug: Ampicillin (antibacterial)  Hetacillin is a prodrug form of ampicillin in which the amide nitrogen and α-amino functionalities have been allowed to react with acetone to give an imidazolidinone ring system.  α-amino group  Absorption, and after absorption regenerates ampicillin. Mannich bases as a prodrug: Rolitetracycline  This approach was also used with the antibiotic tetracycline—the amide nitrogen was allowed to react with formaldehyde and pyrrolidine to give the Mannich base rolitetracycline.  In this case, addition of the basic pyrrolidine nitrogen introduces an additional ionizable functionality  introduces an additional ionizable functionality and increases the water solubility of the parent drug.  The Mannich base hydrolyzes completely and rapidly in aqueous media to give the active tetracycline. Expected to be give IV or IM  Making the amine more lipophilic, is to convert them to imines (Schiff bases) ; however, imines often are too labile in aqueous solution.  The anticonvulsant agent progabide is a prodrug form of γ -aminobutyric acid (GABA), an important inhibitory neurotransmitter.  The lipophilicity of progabide allows the compound to cross the blood– brain barrier; once inside the brain it is hydrolyzed to GABA. Amidines  Amidines also can be acylated to give orally active prodrugs. For example, dabigatran etexilate an orally active antithrombotic and anticoagulant prodrug of the thrombin inhibitor dabigatran which must be administered intravenously. Sulfonamides  Just like amines, sulfonamides can be acylated, but this generates an acidic proton, which makes these compounds amenable to conversion to water-soluble sodium salts.  Second-generation COX-2 inhibitor valdecoxib has been converted to parecoxib sodium, an injectable analgesic drug. Sulindac Chemical drug delivery systems Antiviral agent (Idoxuridine) These drugs serve as substrates for phosphorylating enzymes found in viruses, and the phosphorylated species is the active antiviral agent. The active phosphorylated species is incorporated into viral DNA, disrupting viral replication and, thus, producing the antiviral effect. These drugs do not undergo phosphorylation by mammalian cells, so the prodrug is specific for those sites where it serves as a substrate for phosphorylation enzymes. One of the requirements for site-specific chemical delivery was the proper input/output ratios for prodrug and active drug species at the target. The relative physicochemical properties of prodrug and its phosphorylated derivative suggest an appropriate input/output ratio for site specificity. The prodrug can readily penetrate the virus, and the increased polarity of the phosphorylated derivative would serve to retain that active species inside the virus. The combination of increased polarity and viral retention of the active phosphorylated species likely reduces any human toxicity that might be associated with this active species. Chemical drug delivery systems Pro 2-PAM is the prodrug form of 2-PAM, an important antidote for the phosphate and carbamate acetylcholinesterase inhibitors used in insecticides and nerve gases. Dihdropyridine -prodrug of dopamine The delivery of drugs across the blood—brain barrier has been a significant issue in the design of many therapeutic compounds. Only very lipophilic drugs can cross into the brain without the aid of some active uptake process, such as the one that operates to incorporate essential amino acids into the CNS. The facile oxidation of the dihydropyridine ring system has been extensively investigated as a general process for chemical delivery of a number of drugs to the CNS. This process is a multistep procedure involving delivery of the drug—dihydropyridine derivative to the brain via facile diffusion across the blood—brain barrier, followed by oxidation to the quaternary pyridine cation, which is trapped in the brain. The drug is then released from the pyridine cation by a second metabolic/chemical event. Chemical drug delivery systems Dihdropyridine -prodrug of dopamine 4. Human eye (Dipivefrin) Lipophilic esters of epinephrine, such as the dipivaloyl ester of epinephrine show better corneal penetration following direct application to the eye than the more polar parent drug epinephrine. The esterases necessary for the hydrolysis of the prodrug are readily available in the eye and skin. The more polar drug species, epinephrine is then localized within the lipophilic membrane barriers of the eye, and the drug remains available at the target site to produce its antiglaucoma effect. Chemical drug delivery systems 4. Colon and lower GI tract The delivery of drugs to the colon and lower GI tract has taken advantage of the unique enzymatic processes found in colon bacteria. The glycosidase activity of these bacteria allows hydrolysis of glycoside derivatives of drugs in the colon and provides higher concentrations of active drug. A number of steroid drugs demonstrate increased effectiveness in the lower GI tract following administration as their glycoside derivatives. The polar glycoside derivatives of the steroids are not well absorbed into the bloodstream from the GI tract and remain available to serve as substrates for the bacteria that are found primarily in the human colon. Chemical drug delivery systems Dexamethasone-21-β-D-glucoside (Arrow shows site of action of glycosidase) b. Antitumor agent (Capecitabine) A number of prodrugs for cancer chemotherapy have been designed for selective delivery of active drug to tumor tissue, based on 1) higher levels of activating enzyme in the tumor cell than in normal tissue.2) Many enzymatic systems show higher activity in tumor cells than in normal tissue because of the higher growth rates associated with tumor tissue. Peptidases and proteolytic enzymes are among those systems showing higher activity in and near tumor cells. b. Antitumor agent (Capecitabine) Capecitabine is well absorbed orally and undergoes three activation steps resulting in high tumor concentrations of the active drug. It is first hydrolyzed by liver carboxylesterase, the resulting metabolite being a carbamic acid which spontaneously decarboxylates to 5- deoxy-5-fluorocytidine. The enzyme cytidine deaminase, which is present in the liver and tumors, then transforms 5-deoxy-5- fluorocytidine into 5-deoxy-5-fluorouridine. Transformation into 5- FU is catalyzed by thymidine phosphorylase and occurs selectively in tumor cells. Chemical drug delivery systems 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. Tripartate Drugs (Self-immolative Prodrugs)  Macromolecular Drug Delivery  To address shortcomings associated with small molecules, 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. Disadvantages of Macromolecular Delivery Systems  Macromolecules may not be well absorbed  Alternative means of administration may be needed (injection)  Immunogenicity problems Macromolecular Drug Carriers Synthetic polymers CH2 CH CH2 CH x y OH O O O 8.32 O Aspirin linked to poly(vinyl alcohol) has about the same potency as aspirin, but less toxic. A spacer arm was added, and it was as effective as testosterone. CH3 CH3 CH2 C CH2 C y x C=O C=O O O to enhance - water + Cl sp acer NMe2 S=O solubility arm H3 C O O O 8.35  Poly(-Amino Acid) Carriers O poly(L-glutamine) NH CH C x spacer O O N O O H C CH O 8.37 norethindrone - contraceptive Slow release over nine months in rats General Site-Specific Macromolecular Drug Delivery System Po ly mer ch ain Solubilizer sp acer Ho ming dev ice either hydrophilic or hydrophobic Drug for site specificity 8.38 Site-Specific Delivery of a Nitrogen Mustard O O O NHCH C NHCH C y NH CH C z poly(L-Glu) x space r arm O O O NH O- NH water-solubilizing Ig antibody from rabbit antiserum N Cl Cl against mouse lymphoma cells 8.39  All 5 mice tested were alive and tumor free after 60 days (all controls died).  Also, therapeutic index greatly enhanced (40 fold). Tumor Cell Selectivity  Drug attached to albumin (R = albumin) NH2  Tumor cells take up proteins rapidly. N Proteins broken O N down inside cells, RO O releasing the drug. HO  Shown to inhibit OH growth of Ectomelia cytosine arabinoside (R = H) virus in mouse liver, 8.41 whereas free antitumor inhibitor did not.