Perspectives from Medicinal Chemistry

Nicholas A. Meanwell, Marcus Castreich, Matthias Rarey, Mike Devereux, Paul LA Popelier, Cisbert Schneider, and Peter Willett 

Bioisosteres in Medicinal Chem ry, First Edition. Edited by Nathan Brown 

In a more recent example of the application of isosterism, we have pioneered the use of the cyclopropyl acylsulfonamide moiety as a carboxylic acid isostere in the context of inhibitors of HCV NS3 protease [7, 8]. This moiety confers a significant increase in potency, 50-fold in the matched pair of inhibitors 6 and 7, and has been widely adopted by the industry as a design element [9]. 

A particularly elegant example of the application of bioisosterism designed to avoid toxicity associated with the metabolic activation of a 2,3-diaminopyridine ring has been described in the context of the potent bradykinin B1 receptor antagonist 8, a compound explored for its potential to treat pain [10]. The iterations considered in identifying a replacement for the core heterocycle initially reduced the linker element to the simple ethylene diamine derivative 9 that was ultimately modified to the cyclopropylamino acid amide 12 through the intermediacy of compounds 10 and 11. 

The design and application of bioisosteres in drug discovery has been and will continue to be an important approach to structural modification as medicinal chemists address the wide range of problems that are encountered in contemporary lead optimization initiatives. 

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The series Topics in Medicinal Chemistry is designed to help both novice and experienced medicinal chemists share insights from the drug discovery process. For the novice, the introductory chapter to each volume provides background and valuable perspective on a field of medicinal chemistry not available elsewhere. Succeeding chapters then provide examples of successful drug discovery efforts that describe the most up-to-date work from this field. 

The editors have chosen topics from both important therapeutic areas and from work that advances the discipline of medicinal chemistry. For example, cancer, metabolic syndrome and Alzheimer s disease are fields in which academia and industry are heavily invested to discover new drugs because of their considerable unmet medical need. The editors have therefore prioritized covering new developments in medicinal chemistry in these fields. In addition, important advances in the discipline, such as fragment-based drug design and other aspects of new lead-seeking approaches, are also planned for early volumes in this series. Each volume thus offers a unique opportunity to capture the most up-to-date perspective in an area of medicinal chemistry. 

The main issue with tight binding inhibition, from a medicinal chemistry perspective, is the limitations imposed by this behavior on following SAR. As the inhibitor affinity increases to the point where Arfpp is less than or equal to the enzyme con-... 

The review articles by Schramm (1998, 2003) provide a number of examples of the successful application of this protocol to the design of enzyme-specific transition state-like inhibitors. Among these, the transition state inhibitors of human purine nucleoside phosphorylase (PNP) are particularly interesting from a medicinal chemistry perspective, as examples of these compounds have entered human clinical trials for the treatment of T-cell cancers and autoimmune disorders. 

Vianello, R. (2005) MetaSite understanding metabolism in human cytochromes from the perspective of the chemist. Journal of Medicinal Chemistry, 48, 6970-6979. 

Cruciani, G., Carosati, E., De Boeck, B., Ethirajulu, K., Mackie, C., Howe, T. and Vianello, R. (2005) MetaSite understanding metabolism in human cytochromes from the perspective of the chemist. Journal of Medicinal Chemistry, 48, 6970-6979. 

While not convincing from a statishcal perspective, the results in this section are consistent with a trend high-activity molecules published in the past decade of medicinal chemistry literature are more likely to be found in the large, hydrophobic and poor solubility corner of chemical property space. These results are not consistent with, for example, cell-based [41] and median-based [42] partihoning of biologically active compounds however, such analyses were performed in the presence of inactive compounds selected from MDDR[41] or ACD [42], with quite probably unrelated chemotypes. ACD, the Available Chemicals Directory [43], and MDDR, the MDL Drug Data Report [43], are databases commonly used by the pharmaceuhcal industry. 

From the perspective of organic chemistry, the medicinal chemistry of the bisindole alkaloids derived from Catharanihus roseus (L.) G. Don circumscribes a large and exceedingly diverse collection of structurally complex molecules. There can be no doubt that the breadth and diversity of these compounds is due, in large part, to the remarkable biological... 

Kubinyi H. (2004) Drug discovery from side effects. In H Kubini, G Muller (eds), Chemogenomics in Drug Discovery — A Medicinal Chemistry Perspective, pp. 43-68. Wiley-VCH, Weinheim. 

Lipids are naturally occurring organic molecules, isolated from animal or plant cells by extraction with nonpolar organic solvents. This definition defines lipids in terms of a physical property (solubility) and differs from structural definitions used for proteins or carbohydrates. Not surprisingly, lipids are highly varied in their structure from the medicinal chemistry perspective, there are five classes of lipids ... 

The various topics discussed in this book have up to this point been arranged as far as possible on the basis of chemical structure compounds that contain one oxygen and one nitrogen atom have, for example, as a general rule preceded those that contain two nitrogen atoms. The fact that virtually all of the entities that follow show CNS activity combined with the circumstance that phenothiazines comprise a large part of this section require a departure from that approach. The serendipitous discovery of the antipsychotic activity of the phenothiazines in the early 1950s virtually opened the modern era of medicinal chemistry. These will thus be discussed at the outset to preserve historical perspective. 

Since the appearance of computer-aided structure-activity studies, the term pharmacophore has become one of the most popular words in medicinal chemistry. However, depending on their scientific background and/or traditions, the different medicinal chemistry groups attribute various meanings to this term. Therefore, it appeared necessary to devote a brief paragraph to the definition of the word pharmacophore, and this is followed by a historical perspective and finally by some comments from a medicinal chemistry practitioner. 

This subset was further investigated using the slower modeling methods to try to identify potential actives, known as plausible hits. An example of a molecule selected from the results of a docking experiment is shown in Fig. 4.8. This molecule had a similarity score of 0.93 to an active and is shown docked with the typical kinase inhibitor binding pattern. Both the active and the plausible hit are not drug-like from a medicinal chemistry perspective, but this example demonstrates well how the Feature Tree descriptor captures similarity between two molecules. 

From a chemist s perspective, it is necessary to interactively analyze and visualize screening results by structural scaffolds to identify chemical series that can be synthetically optimized. Depending on the business process, interactive HTS analysis from a medicinal chemistry perspective can be performed at any stage—after primary, concentration response, or secondary screening (Figure 14.1). 

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