Prodrugs Medicinal Chemistry I 1

Prodrugs  Are inactive compounds converted to the active form in vivo.  Useful for drugs with undesirable physicochemical property. 2

Undesirable Properties Physical Properties: a)Poor aqueous solubility b)Low lipophilicity c)Chemical instability d)Acid Sensitivity e)Poor Membrane Permeability (poor absorption) f)Toxicity (non-selective bioactivity) g)Bad Taste h)Short Duration of Action i)Non-site specific 3

Prodrugs activation mechanisms Variety of mechanisms by which prodrug can be converted into active drug: 1. Metabolizing enzymes (phosphotase, esterases, peptidase) Interpatient variable 2. Chemical activation (Hydrolysis, decarboxylation, light activation) Stability issues 3. Mixture of both Two important points: 1. The prodrug should be effectively converted to the active form once absorbed in the blood. 2. Cleavable groups are non toxic. 4

 Not all prodrugs are activated by metabolic enzymes.  Photodynamic therapy involve the use of an external light to activate prodrugs.

Prodrugs classification Can be classified into three categories: 1. Carrier-linked prodrugs - Carrier-linked prodrugs are drugs that have been attached through a metabolically labile linkage to another molecule, the so-called promoiety, which is not necessary for activity but may impart some desirable property to the drug 6

Prodrugs classification 2. Mutual prodrugs - In this type, both the drug and the carrier has activity 7

Produrgs classification 3. Bioprecursor prodrugs - contain no promoiety but rather rely on metabolism to introduce the functionality necessary to create an active species 8

Carrier-linked prodrugs Prodrugs functional groups 9

Prodrugs functional groups - Esters  The most common type of prodrug because of the ease with which the ester can be hydrolyzed or formed.  Esterase enzymes present in plasma and other tissues that are capable of hydrolyzing a wide variety of ester linkages  Can add lipophilicity or hydrophilicity to the drug  Increasing lipophilicity of the compound may yield a number of benefits, including increased absorption, decreased dissolution in the aqueous environment of the stomach, longer duration of action, and reducing bad taste 10

Improve membrane permeability Problem: - Epinephrine is poorly absorbed through eye tissues - Catechols are unstable Solution: The increased lipophilicity relative to epinephnine allows the drug to move across the membrane of the eye easily and achieve higher intraocular concentrations The steric bulk of pivalic acid slows down the hydrolysis 11

Improve Membrane Permeability  Ampicillin is poorly absorbed from the GI tract (~30% absorbed)WHY???  The carboxylic acid functional group (COOH): Binds the drug to a receptor via ionic or hydrogen bonding. An ionizable group may prevent drug from crossing a fatty cell membrane.Solution: Convert the acid function to an ester moiety. The less polar ester can cross fatty cell membranes. The ester group will be hydrolyzed back to the free acid by the esterase in the blood. 12

Ampicillin activation In Vivo 13 Esterase

Masking bad taste Problem: Water soluble drugs when dissolve in the mouth could lead to bad taste - This cause low compliance (pediatric) Solution: A prodrug with reduced water solubility does not dissolve to any appreciable extent in the mouth and, therefore, does not interact with taste receptors. 14

Prodrugs for stability Problem: propanolol undergo extensive first pass metabolism (glucuronidation) Solution: adding ester group on the alcohol will protect it from metabolism

Prodrugs for stability

Increasing hydrophilicity Increase the water solubility of drugs, making them more suitable for parenteral or oral administration when high water solubility is desirable 17 Clindamycin Phosphate

Improve membrane permeability Peptide carrier systems

Prodrug Protein Carrier in BBB (Blood Brain Barrier) 19

Drugs with amine moiety The amide derivative is not a suitable choice in most of the case (WHY?)….Stable bond toward hydrolysis compared to the ester bond.

Drugs with amine moiety Prodrug to increase lipophilicity 21

Drugs with amine moiety Prodrugs to increase water solubility

Prolong The Activity Prodrug Sustained Action N-demethylation Metabolism 23

Azo prodrugs from amine 24