Privileged Scaffolds in Medicinal Chemistry: An Introduction

ELIEZER J. BARREIRO

Laboratório de Avaliação e Síntese de Substâncias Bioativas, Universidade Federal do Rio de Janeiro, CCS, Cidade Universitária, PO Box 68.006, ZIP 21941-910, Rio de Janeiro, RJ, Brazil

Email: ejbarreiro@ccsdecania.ufrj.br

1.1 Introduction

The 20th century has seen significant technological advances, as demonstrated by comparing technology's impact on everyday life at the beginning and end of the century. Many agree that this evolution can hardly have been predicted, nor the drastic changes to several scientific concepts. In many sectors, technological and scientific advancements made throughout the century were spectacular, in particular, in the ways in which we communicate, which is probably due to the evolution of computer science, among others.

The drug discovery process has also undergone huge changes and when we compare, even superficially, the stage that was achieved by the end of the century with that of earlier years, it is clear that there are significant differences. For example, at the end of the 19th century and beginning of the 20th century, when acetylsalicylic acid (ASA 1; Figure 1.1), which may be considered the first drug to be industrially produced, was discovered, there was a completely different scientific environment to that of 1997, when imatinib (2, Figure 1.1), a powerful tyrosine-kinase (TK) inhibitor was created in Basel, Switzerland, in the Ciba-Geigy laboratories (currently Novartis) and was launched in 2001 for the treatment of chronic myeloid leukemia. In the interval between both discoveries, we can see scientific and technological achievements that altered the paradigms of the drug discovery process. Obviously, most drugs that are now part of the contemporary therapeutic arsenal were created in the past century. Significant innovative examples include:

• propranolol (3, Figure 1.1), created by Black and co-workers in the ICI laboratories in England in 1964;

• cimetidine (4, Figure 1.1), created in 1975 at Smith, Kline & French (SK&F);

• captopril (5, Figure 1.1), created by Ondetti and Cushman at Squibb laboratories; and,

• simvastatin (6, Figure 1.1), created by Patchett and collaborators at Merck in 1998.

All of these examples are the result of research efforts conducted in industrial laboratories and represent first-in-class drugs that are significant therapeutic innovations.

In addition to these discoveries, imatinib was a fantastic therapeutic innovation at the turn of the century (2). It is used now in cancer chemotherapy, and was also created in an industrial research laboratory, involving modern medicinal chemistry strategies supported with HTS techniques. We understand that its discovery in the laboratories of Ciba-Geigy unraveled a new paradigm in which it was realized that multifactor diseases, generally chronic ones, need multitarget drugs. This new way of thinking among medicinal chemists, the discoverers of new drugs, has influenced the adoption of new approaches and the development of new terminology, in the latter half of the last century.

In 1988, Evans published an article which mentioned the term 'privileged structures', describing them as simple structural subunits present in the molecules of several drugs, with distinctive therapeutic uses, or affinities to several different receptors. This terminology has widened in its use, maybe in an excessively liberal way, and terms like 'molecular framework', 'chemotype', 'molecular fragment', and 'molecular scaffold', all of them synonymous, were created. In summary, some of these terms acquired different meanings, and due to current challenges in medicinal chemistry, they may be applied concurrently with other drug discovery techniques, such as molecular docking of fragments elected for the virtual screening in the search of new ligands of determinate targets, or in the construction of intelligent chemical libraries for use in HTS approaches, or to identify ligands, now called hits. The identification of a new hit has widened the notion of molecular optimization through the use of classic medicinal chemistry techniques, to increase the affinity for the target in question, whether in potency or in selectivity. This establishes a certain hierarchy of the initial hit for the ligand, still without proof of concept for the prototype, now with pharmadynamic and pharmakinetic properties identified in functional pharmacological models.

Often the use of the terms 'privileged structure', 'fragment', or 'molecular scaffold' is mixed with the unique identity of each term being determined by molecular weight (in the case of fragments) or by the higher level of molecular simplification of a specific structural subunit for the use of molecular scaffold, here referring to cyclic structural subunits, aromatic or not. Both terms, however, refer to privileged structures. The bio IT experts use each term in a more precise way, which is mainly due to the function of the form or the elected molecular topology for each study.

The evolution observed in the area of drug design and discovery throughout the last century may enable us to consider medicines as one of the biggest inventions of that century, because practically the entire contemporary therapeutic arsenal was invented or...