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

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

Spray-dried dispersions (SDDs) of low-solubility drugs have been prepared using the polymer hydroxypropyl methylcellulose acetate succinate (HPMCAS). For a variety of drug structures, these SDDs provide supersaturation in in vitro dissolution determinations and large bioavailability increases in vivo. In bile-salt/lecithin in vitro solutions, these SDDs provide amorphous drug/polymer colloids and an increased concentration of free drug and drug in micelles relative to crystalline or amorphous drug. As dry powders, the SDDs are a single amorphous phase in which the drug remains amorphous and dispersed and does not crystallize over storage times relevant for practical drug products. A melting temperature (Tm)/glass-transition temperature (Tg) (K/K) versus log P map for 139 compounds formulated as SDDs provides a perspective on an appropriate formulation strategy for low-solubility drugs with various physical properties.

http://pubs.acs.org/doi/pdf/10.1021/mp8000793

Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: an overview.

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

A concept of “all or nothing” inspired the innovation of a one-pill-once-daily HIV treatment. Atripla® was the one pill that combined efavirenz, emtricitabine, and tenofovir disoproxil fumarate to become the first daily single tablet regimen that forever simplified HIV treatment to enhance patient compliance and thus, sustained viral suppression. The making of Atripla incorporated dry granulation and bilayer compression technologies to achieve stability and bioequivalence in an optimal pill size. In 2011, there lacked a standard of care for chronic hepatitis C infections that was safe, simple, short, free of interferon and ribavirin, and with high cure rates. A fixed-dose combination of ledipasvir and sofosbuvir was developed and approved in 2014 to be the first complete daily single tablet regimen for CHC genotype 1 infection. A spray-drying process for particle morphology engineering in a polymer matrix was used for improving bioavailability.

Reza Oliyai

Papers

Prodrugs: design and clinical applications

The making of the one pill—Developing single tablet regimens for HIV and for HCV