The Medicinal Chemist’s Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates

The Medicinal Chemist's Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates

Prodrugs are bioreversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect. In both drug discovery and development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents. About 5-7% of drugs approved worldwide can be classified as prodrugs, and the implementation of a prodrug approach in the early stages of drug discovery is a growing trend. To illustrate the applicability of the prodrug strategy, this article describes the most common functional groups that are amenable to prodrug design, and highlights examples of prodrugs that are either launched or are undergoing human trials.

Prodrugs: design and clinical applications

Ionic liquids are remarkable chemical compounds, which find applications in many areas of modern science. Because of their highly tunable nature and exceptional properties, ionic liquids have become essential players in the fields of synthesis and catalysis, extraction, electrochemistry, analytics, biotechnology, etc. Apart from physical and chemical features of ionic liquids, their high biological activity has been attracting significant attention from biochemists, ecologists, and medical scientists. This Review is dedicated to biological activities of ionic liquids, with a special emphasis on their potential employment in pharmaceutics and medicine. The accumulated data on the biological activity of ionic liquids, including their antimicrobial and cytotoxic properties, are discussed in view of possible applications in drug synthesis and drug delivery systems. Dedicated attention is given to a novel active pharmaceutical ingredient-ionic liquid (API-IL) concept, which suggests using traditional drugs in ...

Biological Activity of Ionic Liquids and Their Application in Pharmaceutics and Medicine.

Ocular drug delivery has been a major challenge to pharmacologists and drug delivery scientists due to its unique anatomy and physiology. Static barriers (different layers of cornea, sclera, and retina including blood aqueous and blood–retinal barriers), dynamic barriers (choroidal and conjunctival blood flow, lymphatic clearance, and tear dilution), and efflux pumps in conjunction pose a significant challenge for delivery of a drug alone or in a dosage form, especially to the posterior segment. Identification of influx transporters on various ocular tissues and designing a transporter-targeted delivery of a parent drug has gathered momentum in recent years. Parallelly, colloidal dosage forms such as nanoparticles, nanomicelles, liposomes, and microemulsions have been widely explored to overcome various static and dynamic barriers. Novel drug delivery strategies such as bioadhesive gels and fibrin sealant-based approaches were developed to sustain drug levels at the target site. Designing noninvasive sustained drug delivery systems and exploring the feasibility of topical application to deliver drugs to the posterior segment may drastically improve drug delivery in the years to come. Current developments in the field of ophthalmic drug delivery promise a significant improvement in overcoming the challenges posed by various anterior and posterior segment diseases.

Ocular Drug Delivery

Carbohydrates are the most abundant natural products. Besides their role in metabolism and as structural building blocks, they are fundamental constituents of every cell surface, where they are involved in vital cellular recognition processes. Carbohydrates are a relatively untapped source of new drugs and therefore offer exciting new therapeutic opportunities. Advances in the functional understanding of carbohydrate-protein interactions have enabled the development of a new class of small-molecule drugs, known as glycomimetics. These compounds mimic the bioactive function of carbohydrates and address the drawbacks of carbohydrate leads, namely their low activity and insufficient drug-like properties. Here, we examine examples of approved carbohydrate-derived drugs, discuss the potential of carbohydrate-binding proteins as new drug targets (focusing on the lectin families) and consider ways to overcome the challenges of developing this unique class of novel therapeutics.

From carbohydrate leads to glycomimetic drugs

Synthesis, in vitro and in vivo characterization of novel ethyl dioxy phosphate prodrug of propofol.

Hydroxyimine derivatives of ketoprofen (1) and nabumetone (2) were synthesized and evaluated in vitro and in vivo as cytochrome P450-selective intermediate prodrug structures of ketones. 2 released nabumetone in vitro in the presence of isolated rat and human liver microsomes and in different recombinant human CYP isoforms. Bioconversion of 2 to both nabumetone and its active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA), was further confirmed in rats in vivo. Results indicate that hydroxyimine is a useful intermediate prodrug structure for ketone drugs.

Evaluation of hydroxyimine as cytochrome P450-selective prodrug structure.

A cyclic phosphate prodrug of a descriptive molecule containing an alcohol functionality was designed, synthesized and characterized in vitro as a cytochrome P450 (CYP) -selective prodrug. To achieve efficient CYP-oxidation and prodrug bioconversion, 1,3-cyclic propyl ester of phosphate was designed to have a C4-aryl substituent and synthesized using phosphorus(III) chemistry. The two-step bioconversion of the cyclic phosphate prodrug was evaluated in vitro using human liver microsomes and recombinant CYP enzymes. This cyclic phosphate prodrug underwent initial CYP-catalyzed oxidation and was mainly catalyzed by the CYP3A4 form. The hydroxylated product was slowly converted to a ring-opened intermediate, which subsequently transformed by β-elimination reaction to a free phosphate. The free phosphate was further dephosphorylated by microsomal phosphatases, releasing the parent molecule with a free hydroxyl group. The cyclic phosphate was reasonably stable in buffer solutions at the pH range 1.0−9.0. Since CYP enzymes reside predominantly in the liver and secondarily in the small intestine, the results indicate that cyclic phosphate prodrugs represent a very feasible liver- or intestinal-targeted drug delivery strategy for drug molecules containing an alcohol functionality. This may potentially improve the efficacy and the safety profile of the alcoholic parent drugs.

Novel Cyclic Phosphate Prodrug Approach for Cytochrome P450-activated Drugs Containing an Alcohol Functionality

The requirements demanded with respect to the potency and safety of novel chemical entities are increasing and correspondingly the financial investments needed for developing a new drug are exploding. Finding ways to overcome the poor drug-like properties, such as solubility, permeability and toxicity are essential in diminishing the numbers of failures, and thus reducing the costs of drug development. In many cases prodrugs may offer a way to overcome the poor drug-like properties of a very potent lead and provide the opportunity to convert a non-developable molecule into a potent candidate for clinical use. Prodrugs are pharmacologically inactive molecules that require an enzymatic and/or chemical transformation before release of a pharmacologically active parent drug in vivo. The prodrug approach can be applied to a variety of drug molecules, administration routes and formulations, and is one way to improve the physicochemical, pharmaceutical and biopharmaceutical properties of pharmacologically potent structures and to overcome barriers to a drug's usefulness. In the present study, several different prodrug structures were synthesized to achieve improved drug delivery, including hydroxyimines, ethylidene phosphates and monomethyl phosphate esters. The model drugs used in this study were nabumetone, ketoprofen and propofol. The physicochemical and pharmaceutical properties of novel prodrug structures, including aqueous solubility, lipophilicity, chemical stability and enzymatic release of the parent drug were evaluated in vitro and the bioconversion of the prodrug to the parent drug was further confirmed in vivo in rats. Hydroxyimine was shown to be bioconverted to the corresponding ketone by microsomal cytochrome P450-enzymes both in vitro and in vivo and the released nitric oxide evoked no acute liver toxicity after peroral administration in rats. Hydroxyimine is thus a potential intermediate prodrug structure, especially for ketone drugs. However, the chemical and the enzymatic hydrolysis rate of different hydroxyimines to the parent ketone drug varied extensively between the two different model compounds, suggesting that the chemical environment around the hydroxyimine structure affects to the applicability of hydroxyimine prodrug structure. A method to synthesize of 1-chloroethyl phosphates and phosphoramidates was developed. This method is a versatile and simple way to prepare 1-chloroethyl phosphates and phosphoramidates either under normal temperature and pressure conditions or using microwave-assisted synthesis. 1-Chloroethyl phosphates could not be used as starting materials of ethylidene phosphate prodrugs as such. However, the synthesis method developed for 1-chloroethyl phosphates could be modified to the synthesis of ethylidene phosphate prodrug of propofol. Ethylidene phosphate propofol increased the aqueous solubility of propofol and enzymatically released propofol in vitro and in vivo in rats, thus proving to be a suitable water-soluble prodrug of propofol for i.v. administration. Bioconversion of the ethylidene phosphate prodrug releases acetaldehyde, which is less toxic than the formaldehyde released from traditionally used phosphonooxymethyl prodrugs. The monomethyl phosphate and phosphonooxymethyl ester prodrugs of propofol did not release the parent drug in vitro or in vivo, probably due to inability of propofol to act as a substrate for the phosphodiesterases. Thus, the monoalkyl esters of phosphates do not seem to be suitable as versatile prodrug structures, but more studies with nucleotide-type model compound are needed to confirm this speculation. In conclusion, the present study provided useful information of several novel prodrug structures. In particular, the ethylidene phosphate structure holds a great promise for further development of phosphate prodrugs. National Library of Medicine Classification: QV 744, QV 785, QV 38 Medical Subject Headings: Drug Design; Prodrugs / chemical synthesis; Molecular Structure; Drug Delivery Systems; Ketoprofen; Propofol; Solubility; Drug Stability; Pharmacokinetics; Phosphates; Microwaves "Prodrug research needs more imagination and less dependency on what has been tried in the past". Valentino J. Stella in Advanced Drug Delivery Reviews, 1996

Hanna Kumpulainen

Papers

Prodrugs: design and clinical applications

Synthesis, in vitro and in vivo characterization of novel ethyl dioxy phosphate prodrug of propofol.

Evaluation of hydroxyimine as cytochrome P450-selective prodrug structure.

Novel Cyclic Phosphate Prodrug Approach for Cytochrome P450-activated Drugs Containing an Alcohol Functionality

Novel Prodrug Structures for Improved Drug Delivery