The role of medicinal chemistry in drug research

Classical medicinal chemistry, that is molecular modifications of existing bioactive compounds, leading to me-too drugs with value added and often to me-too drugs which will never reach the market or to drugs in another pharmacological field than that originally intended, will be with us for a long time to come. The ultimate goal, however, is of course rational or at least semi-rational drug design. In some instances this goal seems to have already been reached as in the case of angiotensin-converting enzyme inhibitors and H₂ antagonists. In the (near) future results from the steady progress in molecular biology in combination with computer-assisted drug modelling — possibly coupled with artificial intelligence techniques — will help the medicinal chemist in his efforts to attain this goal.     

Drug resistance and the microenvironment: nature and nurture.

Drug resistance remains a major obstacle to the successful use of chemotherapeutic drugs for cancer therapy. It is well documented that cancer cells can adapt to the presence of chemotherapeutic agents through mutations or expression changes of key genes that control drug metabolism or response to damage. In addition, it is becoming increasingly apparent that the tumor microenvironment can have an important impact on the success of chemotherapy. Indeed, cell-cell and cell-matrix interactions can influence the cancer cells sensitivity to apoptosis and affect drug resistance. A model is proposed in which the tumor cells may actively reorganize their environment to maximize their survival in the presence of anticancer agents.     

Cannabinoids: occurrence and medicinal chemistry

With an inventory of several hundreds secondary metabolites identified, Cannabis sativa L. (hemp) is one of the phytochemically best characterized plant species. The biomedical relevance of hemp undoubtedly underlies the wealth of data on its constituents and their biological activities, and cannabinoids, a class of unique meroterpenoids derived from the alkylation of an olivetollike alkyl resorcinol with a monoterpene unit, are the most typical constituents of Cannabis. In addition to the well-known psychotropic properties of Δ(9)-THC, cannabinoids have been reported to show potential in various fields of medicine, with the capacity to address unmet needs like the relief of chemotherapy-derived nausea and anorexia, and symptomatic mitigation of multiple sclerosis. Many of the potential therapeutic uses of cannabinoids are related to the interaction with (at least) two cannabinoid G-protein coupled receptors (CB1 and CB2). However, a number of activities, like the antibacterial or the antitumor properties are non totally dependent or fully independent from the interaction with these proteins. These pharmacological activities are particularly interesting since, in principle, they could be easily dissociated by the unwanted psychotropic effects. This review aims at giving readers a survey of the more recent advances in both phytochemistry of C. sativa, the medicinal chemistry of cannabinoids, and their distribution in plants, highlighting the impact that research in these hot fields could have for modern medicinal chemistry and pharmacology.     

Etoposide: discovery and medicinal chemistry

Etoposide is an antitumor agent currently in clinical use for the treatment of small cell lung cancer, testicular cancer and lymphomas. Since the introduction of etoposide in 1971, its mechanism of action and potent antineoplastic activity has served as the impetus for intensive research activities in chemistry and biology. This drug acts by stabilizing a normally transient DNA-topoisomerase II complex, thus increasing the concentration of double-stranded DNA breaks. This phenomenon triggers mutagenic and cell death pathways. The function of topoisomerase II is understood in some detail, as is the mechanism of inhibition of etoposide at a molecular level. Etoposide has shortcomings of limited neoplastic activity against several solid tumors such as non-small cell lung cancer, cross-resistance to MDR tumor cell lines and low bioavailability. The design and synthesis of etoposide analogs is an activity of fundamental interest to the field of cancer chemotherapy. In the first part, this article is a survey of the discovery of etoposide, the DNA topoisomerase II structure and mechanism, and the models for drug-enzyme interaction. The last part is concerned with the search for new etoposide analogs based upon an empirical design.     

Rediscovering the sweet spot in drug discovery

Advances over the past decade in drug discovery technologies have not yet led to an increase in productivity. We analyzed the reasons that have led to this juncture and identify the selection of the right target and the right lead as crucial. New approaches are required to take full advantage of the genomics revolution. For targets, methods are becoming available for high-throughput proteome analysis and pathway characterization that synergize with studies of disease association and differential expression. For leads, methods are being developed that 'reverse' the high-throughput screening paradigm by mapping drugs and drug-like compounds back onto the proteome. The synergy between pathway mapping and compound mapping could allow the pharmaceutical and biotechnology industries to rediscover the sweet spot of research productivity.     

Polyethylenimine in medicinal chemistry

Polyethylenimine (PEI), an organic branched or linear polyamine polymer, has been successfully used in the past for DNA complexation and transfection in vitro and in vivo into several cell lines and tissues. PEI was also applied in different fields from gene therapy and several studies have emphasized the importance of this polymer in medicinal chemistry. In this brief critical review the uses and applications of this versatile polymeric molecule will be discussed.     

Trends in medicinal chemistry

The Society for Medicines Research held a meeting on Trends in Medicinal Chemistry on November 30, 2000, in Stevenage, U.K., with the goal of alerting researchers to emerging areas of chemistry and novel classes of compounds likely to lead to new approaches to the treatment of disease. Speakers from nine pharmaceutical companies described areas of research that included phosphodiesterase inhibitors, adenosine receptor ligands, VEGF RTK inhibitors, RNA-protein interaction inhibitors, NMT inhibitors, anti-HCV agents and antidepressants.     

Proteomics in medicinal chemistry

Proteomics is becoming an important research area for studying protein expression patterns induced by different external stimuli. An important aspect of proteomics is to identify and quantify proteins. Many new technologies and techniques have been developed in this field and have been applied to various aspects of drug discovery.     

Trends in medicinal chemistry

On December 3, 1998, the Society for Medicines Research held a meeting entitled Trends in Medicinal Chemistry at the National Heart and Lung Institute, London. The meeting was conceived to alert researchers to compounds in early development or new discoveries likely to lead to new approaches to disease treatment in the near future. Presentations covered potential therapies for CNS disorders, through immune disease and cancer to cardiovascular diseases. Specific new discoveries described at the meeting included the antipsychotic agent ORG-23366; the anticonvulsants SB-204269, SB-258229 and SB-270664; the tyrosine kinase inhibitors CT-5269 and CT-4694; VEGF inhibitors from Zeneca; the elastase inhibitor GW-311616A; a serine protease inhibitor from Roche; the MMPI D-2163; two antimigraine follow-ons to rizatriptan, L-775606 and L-785103; the P(2T) inhibitor AR-C69931MX and a follow-on compound; and the PDE5 inhibitor sildenafil.     

Automation in medicinal chemistry

The implementation of appropriate automation can make a significant improvement in productivity at each stage of the drug discovery process, if it is incorporated into an efficient overall process. Automated chemistry has evolved rapidly from the 'combinatorial' techniques implemented in many industrial laboratories in the early 1990's which focused primarily on the hit discovery phase, and were highly dependent on solid-phase techniques and instrumentation derived from peptide synthesis. Automated tools and strategies have been developed which can impact the hit discovery, hit expansion and lead optimization phases, not only in synthesis, but also in reaction optimization, work-up, and purification of compounds. This article discusses the implementation of some of these techniques, based especially on experiences at Millennium Pharmaceuticals Research and Development Ltd.     

Oxadiazoles in medicinal chemistry

Oxadiazoles are five-membered heteroaromatic rings containing two carbons, two nitrogens, and one oxygen atom, and they exist in different regioisomeric forms. Oxadiazoles are frequently occurring motifs in druglike molecules, and they are often used with the intention of being bioisosteric replacements for ester and amide functionalities. The current study presents a systematic comparison of 1,2,4- and 1,3,4-oxadiazole matched pairs in the AstraZeneca compound collection. In virtually all cases, the 1,3,4-oxadiazole isomer shows an order of magnitude lower lipophilicity (log D), as compared to its isomeric partner. Significant differences are also observed with respect to metabolic stability, hERG inhibition, and aqueous solubility, favoring the 1,3,4-oxadiazole isomers. The difference in profile between the 1,2,4 and 1,3,4 regioisomers can be rationalized by their intrinsically different charge distributions (e.g., dipole moments). To facilitate the use of these heteroaromatic rings, novel synthetic routes for ready access of a broad spectrum of 1,3,4-oxadiazoles, under mild conditions, are described.     

The impact of click chemistry in medicinal chemistry

Introduction: The copper(I)-catalyzed 1,3-dipolar cycloaddition of alkynes and azides to form 1,2,3-triazoles is the most popular reaction in click chemistry. This reaction is also near-perfect, in terms of its robustness, due to the high degree of reliability and complete specificity. Furthermore, this reaction has been used increasingly in drug discovery, because the formed 1,2,3-triazole can act as both a bioisostere and a linker.

Areas covered: This review provides an overview of a most important click reaction, 1,3-dipolar cycloadditions of alkynes and azides, in the drug discovery.

Expert opinion: Click chemistry is a very powerful tool, in the drug discovery, because it is very efficient in the creation of compound libraries through combinatorial methodology. However, the 1,2,3-triazole ring itself is not a commonly used pharmacophore and has rarely been found in marketed drugs, demonstrating that there are still some limitations during the use of 1,2,3-triazole in the molecules of drug candidates. Hopefully, in the next decade, we will witness the emergence of 1,2,3-triazole-bearing drugs on the market as this click reaction is used more and more widely in the drug discovery.     

The impact of click chemistry in medicinal chemistry

INTRODUCTION: The copper(I)-catalyzed 1,3-dipolar cycloaddition of alkynes and azides to form 1,2,3-triazoles is the most popular reaction in click chemistry. This reaction is also near-perfect, in terms of its robustness, due to the high degree of reliability and complete specificity. Furthermore, this reaction has been used increasingly in drug discovery, because the formed 1,2,3-triazole can act as both a bioisostere and a linker. AREAS COVERED: This review provides an overview of a most important click reaction, 1,3-dipolar cycloadditions of alkynes and azides, in the drug discovery. EXPERT OPINION: Click chemistry is a very powerful tool, in the drug discovery, because it is very efficient in the creation of compound libraries through combinatorial methodology. However, the 1,2,3-triazole ring itself is not a commonly used pharmacophore and has rarely been found in marketed drugs, demonstrating that there are still some limitations during the use of 1,2,3-triazole in the molecules of drug candidates. Hopefully, in the next decade, we will witness the emergence of 1,2,3-triazole-bearing drugs on the market as this click reaction is used more and more widely in the drug discovery.     

Research in the division of medicinal chemistry

Within the Center for Bio-Pharmaceutical Sciences research on medicinal chemistry is centered around two themes: receptor recognition and photochemistry of drugs. Extremely little is known about the conformation of receptor recognition sites. The approach that should lead to a more detailed knowledge is outlined. Similarly the interaction between enzymes and their inhibitors will be studied. The photochemistry of drugs can be useful (phototherapy) or harmful (phototoxicity). The phototoxicity of benzodiazepines was found to be attributable to the formation of oxaziridines on theN-oxide groups.     

Sol-gel chemistry in medicinal science

The sol-gel process is an inorganic polymerization process taking place in mild conditions, allowing the association of mineral phases with organic or biological systems. The possibility to immobilize drugs, enzymes, antibodies and even whole cells without loss of their biological activity led to the development of diagnostic tools, drug delivery carriers as well as new hosts for artificial organ design. These systems take profit from the wide variety of chemical compositions, dimensions and forms that can be achieved via sol-gel chemistry. Recent advances involve multi-functional "smart" devices combining biocompatibility, biological activity and stimuli-responsive materials. The design of such novel devices with significant added value when compared to current products is probably a key factor when foreseeing industrial developments of sol-gel materials in medicinal science.     

Phosphate isosteres in medicinal chemistry

The phosphate group is at the heart of an enormous number of biological processes. The simple phosphorylation or dephosphorylation of a protein can have a wide range of consequences, including effects on its biological activity, its interaction with other proteins, and on its subcellular location. Abnormal levels of protein phosphorylation have been linked to a wide range of diseases including cancer and diabetes. Consequently, proteins that recognise the phosphate moiety have become an attractive target for therapeutic development. The most prevalent medicinal chemistry research examines the interactions of phosphorylated tyrosine residues; however, the role of phosphate groups on serine or threonine residues, in nucleotides, DNA and RNA, on sugars, and lipid mediators such as lysophosphatidic acid should not be overlooked. Investigations have focused on the non-catalytic phosphotyrosine-recognising domains such as Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains, as well as catalytic proteins such as protein tyrosine phosphatase 1B (PTP1B). The utilisation of the phosphate moiety as part of an inhibitor is severely limited by the enzymatic lability and poor cellular bioavailability of this highly charged recognition element. The development of phosphate isosteres attempts to address these issues by introducing a non-scissile bond and utilizing groups with less charge that are still able to interact favourably with the target protein in much the same way as the phosphate group does. Many phosphate mimics retain the phosphorus atom such as in the highly successful fluoromethylenephosphonates, whereas others have lost the tetrahedral phosphate geometry and are based on the combination of one or more carboxylate groups that generally reduce the overall charge of the molecule. This review focuses on the recent developments and the use of phosphate isosteres in medicinal chemistry, covering roughly the past four years.     

Diversity in medicinal chemistry space

The chemical universe containing organic molecules within a reasonable molecular weight is vast and largely unexplored. Estimations of possible numbers of unique molecules range from 10(13) to 10(180). These numbers have to be compared with the few tens of millions of compounds currently known. Design of libraries that populate the medicinally relevant chemical subspace and tools that help to maximise the chance of identifying leads are necessary. This review describes various molecular representations that lead to the definition of chemical space, drug space or activity space. Strategies for compound selection in such spaces are discussed, as well as potential sources of diversity that could be used to explore the medicinal space in quest of new drugs.