Prodrug Approach – Fifth Year Lecture 2 Mohammed N. Sabir March 2019 9 Prodrug Approach Classification, Chemical Delivery System & Drug Targeting 4/11/2019 Prodrug Approach

Review of the last lecture Prodrug Approach – Fifth Year Lecture 2 Lecture outlines… Review of the last lecture Novel classification system for Prodrugs (PDs) Site selective drug delivery (SSDD) Chemical delivery system (CDS) in drug targeting strategy (DTS) Lecture overview Discussion 4/11/2019 Prodrug Approach

Prodrug Approach – Fifth Year Lecture 2 Some examples on CDSs… Progestin CDS was developed to transport gonadal steroids like estradiol and testosterone to the CNS to avoid its peripheral untoward actions like hypertension and weight gain 4/11/2019 Prodrug Approach

Prodrug Approach – Fifth Year Lecture 2 4/11/2019 Prodrug Approach

Prodrug Approach – Fifth Year Lecture 2 4/11/2019 Prodrug Approach

Classification of PDs based on regulatory perspectives Prodrug Approach – Fifth Year Lecture 2 Classification of PDs based on regulatory perspectives Classification based on regulatory metabolic patterns show risk-benefit assessment of PDs since more information about kinetics and impact of target and metabolic tissue are revealed. 4/11/2019 Prodrug Approach

Prodrug Approach – Fifth Year Lecture 2 Drug-action analysis is based on site and mode of actions, hence the PD classification will be more expressive if based on the site where metabolic activation is achieved. 4/11/2019 Prodrug Approach

Prodrug Approach – Fifth Year Lecture 2 A useful classification for PDs will be a risk-benefit assessment based on the site of action providing insight into the kinetics of the conversion process and contribution of the PD to the product’s safety and efficacy. 4/11/2019 Prodrug Approach

Intracellular metabolic activation is needed Sub-classes:- Prodrug Approach – Fifth Year Lecture 2 Type I PDs… Intracellular metabolic activation is needed Sub-classes:- Type IA (e.g. antiviral nucleosides), activated in target cell. Type IB (e.g. lipid lowering statins), activated in metabolic tissue like liver and lung. 4/11/2019 Prodrug Approach

Extracellular metabolic activation is needed Sub-classes:- Prodrug Approach – Fifth Year Lecture 2 Type II PDs… Extracellular metabolic activation is needed Sub-classes:- Type IIA (e.g. etoposide phosphate), activated in digestive fluids. Type IIB (e.g. valganciclovir), activated in systemic circulation. 4/11/2019 Prodrug Approach

Prodrug Approach – Fifth Year Lecture 2 Type II PDs… Type IIC (e.g. fosamprenavir, ADEPT, GDEPT. VDEPT), activated in the vicinity of the target cell. This type relies on esterases, phosphatases or target directed enzyme. 4/11/2019 Prodrug Approach

Tissue Location of Conversion Prodrug Approach – Fifth Year Lecture 2 Classification of Prodrugs Prodrug Types Site of Conversion Subtypes Tissue Location of Conversion Examples Type I Intracellular A Therapeutic Target Tissues/Cells Type IA: Acyclovir 5-Flurouracil Cyclophosphamide Diethlstilbestrol diphosphate L-Dopa 6-Mercaptopurine Mitomycine C Zidovudine B Metabolic Tissues (liver, GI mucosal cell, lung, etc.) Type IB: Cabamazepine Captopril Carisoprodol Heroin Molsidomine Paliperidone Phenacetin Primidone Psilocybin Suldinac Tetrahydrofurfuryl disulfide Table 1 Classification of Prodrugs 4/11/2019 Prodrug Approach

Tissue Location of Conversion Prodrug Approach – Fifth Year Lecture 2 Classification of Prodrugs Prodrug Types Site of Conversion Subtypes Tissue Location of Conversion Examples Type II Extracellular A GI Fluids Type IIA: Lisdexamfetamine Loperamide oxide Oxyphenisatin Sulfasalazine B Systemic Circulation and Other Extracellular Fluid Compartments Type IIB: Acetylsalicylate Bacampicillin Bambuterol Chloramphenicol succinate Dihydropyridine pralixoxime Dipivefrin Fosphenytoin C Therapeutic Target Tissues/Cells Type IIC: ADEPs GDEPs VDEPs Table 1 Classification of Prodrugs 4/11/2019 Prodrug Approach

When a PD belongs to multiple categories… Prodrug Approach – Fifth Year Lecture 2 Mixed-Type PDs… When a PD belongs to multiple categories… “Type IA/IB” PD, activated in both target cell and metabolic tissue (e.g. statins). 4/11/2019 Prodrug Approach

Mixed types may be parallel “ / ” or sequential “ - ”. Prodrug Approach – Fifth Year Lecture 2 Mixed-Type PDs… Mixed types may be parallel “ / ” or sequential “ - ”. 4/11/2019 Prodrug Approach

Prodrug Approach – Fifth Year Lecture 2 3- “Type IIA-IA” PD when PD converted sequentially, e.g., Tenofovir disoproxil fumarate. Others like ADEPs, VDEPs, GDEPs, nanoparticle – or nanocarrier-linked drugs can be sequential Mixed-Type PDs. 4/11/2019 Prodrug Approach

Strategic goals for improving PD design are:- Prodrug Approach – Fifth Year Lecture 2 Strategic goals for improving PD design are:- 1- If the PD will be converted fast and completely into the parent drug. 2- If the PD contributes to the active drug’s toxicity profile. 4/11/2019 Prodrug Approach

Rev., PDs designed when:- Prodrug Approach – Fifth Year Lecture 2 Rev., PDs designed when:- # Problem Example 1 Bioavailability (poor water solubility) Corticosteroids 2 Poor absorption/permeability Ampicillin 3 High first pass metabolism Propranolol 4 Instability (short ½ life) Dopamine 5 Poor site specificity Anticancers 6 Incomplete absorption Epinephrine 7 Undesirable organoleptic properties Chloramphenicol 8 Formulation difficulties Erythromycin 9 Toxicities Estradiol 4/11/2019 Prodrug Approach

Prodrug Approach – Fifth Year Lecture 2 The major groups of carrier-linked prodrugs are esters and amides; other groups include phosphates, carbamates, carbonates, oximes, imines and N-Mannich bases 4/11/2019 Prodrug Approach

Prodrug Approach – Fifth Year Lecture 2 Common functional groups on parent drugs applied in prodrug design. 4/11/2019 Prodrug Approach

Prodrug Approach – Fifth Year Lecture 2 Ester PDs of [-OH, -COOH & -SH] are the most common types of PDs (49%), modification via esters are made for enhancing lipophilicity. Once penetrate biologic membranes undergo enzymatic hydrolysis by esterases in blood, liver and other organs by:- -Carboxyl esterases -Acetylcholinesterases -Butyrylcholinesterases -Paraoxonases -Arylesterases. 4/11/2019 Prodrug Approach

Prodrug Approach – Fifth Year Lecture 2 4/11/2019 Prodrug Approach

Prodrug Approach – Fifth Year Lecture 2 4/11/2019 Prodrug Approach

Carbonates and carbamates PDs, [-COOH, -OH or NH2]… Prodrug Approach – Fifth Year Lecture 2 Carbonates and carbamates PDs, [-COOH, -OH or NH2]… More stable to hydrolysis when compared to esters and less than amides. Activated by the esterases. 4/11/2019 Prodrug Approach

Prodrug Approach – Fifth Year Lecture 2 4/11/2019 Prodrug Approach

Amides as PDs for [-COOH and –NH2] Prodrug Approach – Fifth Year Lecture 2 Amides as PDs for [-COOH and –NH2] Less applied because of high stability to hydrolysis. Hydrolyzed in vivo by:- -Carboxylesterases, peptidases or proteases. Amides are applied to enhance absorption through specific intestinal uptake transporters. 4/11/2019 Prodrug Approach

Prodrug Approach – Fifth Year Lecture 2 Human Carboxylesterase-2 Hydrolyzes the Prodrug of Gemcitabine (LY2334737) and Confers Prodrug Sensitivity to Cancer Cells [Pratt E., et al., 2013, Cl Ca Res.] Gemcitabine inhibits thymidylate synthetase, leading to inhibition of DNA synthesis and cell death. Gemcitabine is a prodrug so activity occurs as a result of intracellular conversion to two active metabolites, gemcitabine diphosphate and gemcitabine triphosphate by deoxycitidine kinase. Gemcitabine diphosphate also inhibits ribonucleotide reductase, the enzyme responsible for catalyzing synthesis of deoxynucleoside triphosphates required for DNA synthesis. Finally, Gemcitabine triphosphate (diflurorodeoxycytidine triphosphate) competes with endogenous deoxynucleoside triphosphates for incorporation into DNA. 4/11/2019 Prodrug Approach

Prodrug Approach – Fifth Year Lecture 2 4/11/2019 Prodrug Approach

Prodrug Approach – Fifth Year Lecture 2 Ketone derivative including oximes (ketoximes, amidoximes and guanidoximes) providing an These functional groups modify compounds lacking [-OH. –NH2 or –COOH] and enhance membrane permeability. They are hydrolyzed by cytochrome P450. 4/11/2019 Prodrug Approach

[O] P450 Prodrug Approach – Fifth Year Lecture 2 4/11/2019

Lecture overview… Prodrug Approach – Fifth Year Lecture 2 4/11/2019

End of lecture… Thanks for paying attention Any questions? Prodrug Approach – Fifth Year Lecture 2 End of lecture… Thanks for paying attention Any questions? 4/11/2019 Prodrug Approach