Chem Biol Drug Des 2013; 82: 643–668 Review Prodrugs Design Based on Inter- and Intramolecular Chemical Processes Rafik Karaman1,2,* compound satisfies a number of preset criteria to start clinical development. The number of years it takes to intro- 1Bioorganic Chemistry Department, Faculty of Pharmacy, duce a drug to the pharmaceutical market is over 10 years Al-Quds University, P.O. Box 20002, Jerusalem, Palestine with a cost of more than $1 billion dollars (1,2). 2Department of Science, University of Basilicata, Via dell’Ateneo Lucano 10, 85100, Potenza, Italy Modifying the absorption, distribution, metabolism, and *Corresponding author: Rafik Karaman, elimination (ADME) properties of an active drug requires a [email protected] complete understanding of the physicochemical and bio- logical behavior of the drug candidate (3 6). This includes This review provides the reader a concise overview of – the majority of prodrug approaches with the emphasis comprehensive evaluation of drug-likeness involving on the modern approaches to prodrug design. The prediction of ADME properties. These predictions can be chemical approach catalyzed by metabolic enzymes attempted at several levels: in vitro–in vivo using data which is considered as widely used among all other obtained from tissue or recombinant material from human approaches to minimize the undesirable drug physico- and preclinical species, and in silico or computational pre- chemical properties is discussed. Part of this review dictions projecting in vitro or in vivo data, involving the will shed light on the use of molecular orbital methods evaluation of various ADME properties, using computa- such as DFT, semiempirical and ab initio for the design tional approaches such as quantitative structure activity of novel prodrugs. This novel prodrug approach relationship (QSAR) or molecular modeling (7–11). implies prodrug design based on enzyme models that were utilized for mimicking enzyme catalysis. The com- Studies have indicated that poor pharmacokinetics and tox- putational approach exploited for the prodrug design icity are the most important causes of high attrition rates in involves molecular orbital and molecular mechanics the drug development process, and it has been widely (DFT, ab initio, and MM2) calculations and correlations between experimental and calculated values of intra- accepted that these areas should be considered as early as molecular processes that were experimentally studied possible in drug discovery to improve the efficiency and to assign the factors determining the reaction rates in cost-effectiveness of the industry. Resolving the pharmaco- certain processes for better understanding on how kinetic and toxicological properties of drug candidates enzymes might exert their extraordinary catalysis. remains a key challenge for drug developers (12). Key words: Ab initio calculations, design of prodrugs, DFT Thus, the aim is to design drugs that have an efficient calculations, enzyme models, molecular mechanics calcula- permeability to be absorbed into the blood circulation tions, prodrugs (absorption), to reach their target efficiently (distribution), to be quite stable to survive the physiological journey (metab- Received 4 July 2013, revised 13 August 2013 and accepted olism), and to be eliminated in a satisfactory time (elimina- for publication 16 August 2013 tion). In other words, designing a drug with optimum pharmacokinetics properties can be achieved by imple- menting one or more of the following strategies: A drug is defined as a substance, which is used in the diagnosis, cure, relief, treatment, or prevention of disease, Improving Absorption or intended to affect the structure or function of the body. The development of any potential drug starts with the Drug absorption is determined by the drug hydrophilic study of the biochemistry behind a disease for which phar- hydrophobic balance (HLB) value, which depends upon maceutical intervention is seen.a polarity and ionization. Very polar or strongly ionized drugs, having a relatively high HLB values, cannot efficiently cross Drug discovery is a lengthy interdisciplinary endeavor. It is the cell membranes of the gastrointestinal (GI) barrier. a consecutive process that starts with target and lead Hence, they are given by the intravenous (I.V.) route, but discovery, followed by lead optimization and preclinical their disadvantage is being rapidly eliminated. Non-polar in vitro and in vivo studies to evaluate whether a ª 2013 John Wiley & Sons A/S. doi: 10.1111/cbdd.12224 643 Karaman drugs, on the other hand, having a relatively low HLB val- Carbachol (1 in Figure 1), a cholinergic agonist, and cefoxi- ues, are poorly soluble in aqueous media and hence are tin (2 in Figure 1), a cephalosporin, are stabilized in this poorly absorbed through membranes. If they are given by way. (iii) Stereoelectronic modification: Steric hindrance and injection, most probably, they will be retained in fat tissues electronic stabilization have been used together to stabilize (13–21). labile groups. For example, procaine, an ester drug, is quickly hydrolyzed, but changing the ester to the less reac- Generally, the polarity and/or ionization of drug can be tive amide group reduces hydrolysis such as in the cases altered by changing its substituents, and these changes of procainamide (3 in Figure 1) and lidocaine (4 in Figure 1). are classified under the so-called quantitative structure– (iv) Metabolic Blockers: Some drugs are metabolized by activity relationships (QSAR). The following are examples introducing polar functional groups at particular positions in for such changes: (1) variation of alkyl or acyl substituents their skeleton. For example, megestrol acetate (5 in Figure and polar functional groups to vary polarity, (1) variation of 1), an oral contraceptive, is oxidized at position 6 to give N-alkyl substituents to vary pKa; acidic drugs with low hydroxyl group at this position; however, replacing the pKa and basic drugs with high pKa values tend to be ion- hydrogen at position 6 with a methyl group blocks its ized and are poorly absorbed through membrane tissues, metabolism, and consequently it results in prolonging its (2) variation of aromatic substituents to vary pKa: The pKa duration of action. (v) Removal of susceptible metabolic of aromatic amine or carboxylic acid can be varied by groups: Certain chemical moieties are particularly suscepti- adding electron donating or electron withdrawing groups ble to metabolic enzymes. For example, a methyl group on to the ring. The position of the substituent is important too aromatic rings is often oxidized to carboxylic acid, which if the substituent interacts with the ring through resonance then results in a rapid elimination of the drug from the and (3) bioisosteres for polar groups; carboxylic acid is a body. Other common metabolic reactions include aliphatic highly polar group which can be ionized and hence and aromatic C-hydroxylation, O and S-dealkylations, N- decreases the absorption of any drug containing it. To and S-oxidations, and deamination. (vi) Group Shifts: overcome this problem, blocking the free carboxyl group Removing or replacing a metabolically vulnerable group is by making the corresponding ester prodrug or replacing it feasible if the group concerned is not involved in important with a bioisostere group, which has similar physiochemical binding interactions within the active site of the receptor or properties and has advantage over carboxylic acid in enzyme. If the group is important, then different strategy regard to its pKa, such as 5-substituted tetrazoles, is either masking the vulnerable group using a prodrug or essential; 5-substituted tetrazole ring contains acidic pro- shifting the vulnerable group within the molecule skeleton is ton such as carboxylic acid and is ionized at pH 7.4. On undertaken. Salbutamol was developed in 1969 from its the other hand, most of the alkyl and aryl carboxylic analog neurotransmitter, norepinephrine, using this tactic. groups have a pKa in the range of 2–5 (13–28). Norepinephrine is metabolized by methylation of one of its phenolic groups by catechol O-methyl transferase. The other phenolic group is important for receptor-binding inter- Improving Metabolism action. Removing the hydroxyl or replacing it with a methyl group prevents metabolism but also prevents hydrogen There are different strategies that can be utilized to bonding interaction with the binding site. While moving the improve drug metabolism: (i) steric shields: Some func- vulnerable hydroxyl group out from the ring by one carbon tional groups are more susceptible to chemical and enzy- unit as in salbutamol makes, this compound unrecogniz- matic degradation than others. For example, esters and able by the metabolic enzyme, but not to the receptor- amides are much more affordable to hydrolysis than others binding site (prolonged action) and (vii) ring variation; some such as carbamates and oximes. Adding steric shields to ring systems are often found to be susceptible to metabo- these drugs increases their stability. Steric shields were lism, and so varying the ring can often improve metabolic designed to hinder the approach of a nucleophile or a stability. For example, replacement of the imidazole ring, nucleophilic center on an enzyme to the susceptible which is susceptible to metabolism in tioconazole (6 in Fig- group. These usually involve the addition of a bulky alkyl ure 1) with 1,2,4-triazole ring, gives fluconazole (7 in Figure group such as t-butyl close to the functional group. 1) with improved stability. (ii) Electronic effects of bioisosteres: This approach is used to protect a labile functional group by electronic stabiliza- Making drug less resistance to drug metabolism: drug that tion. For example, replacing the methyl group of an ester is extremely stable to metabolism and is very slowly elimi- with an amine group gives a urethane functional group, nated can cause problems in a similar manner to that sus- which is more stable than the parent ester. The amine ceptible to metabolism, thus resulting in an increase in group has the same size and valance as the methyl group; toxicity and adverse effects.