Medicinal bioisostere replacement

The thiocarbonyl group is a classic bioisosteric replacement for the carbonyl group which has been widely exploited in medicinal chemistry. This is illustrated with the preparation of thioketones derived from thiocolchicine283 and isothiocolchicine284 which exhibited high antitubulin activity (equation 38). 

When a lead compound is first discovered for a particular disease state, it often lacks the required potency and pharmacokinetic properties suitable for making it a viable clinical candidate. These may include undesirable side effects, physicochemical properties, other factors that affect oral bioavailability (see Chapter 9), and adverse metabolic or excretion properties. These undesirable properties could be the result of specific functional groups in the molecule. The medicinal chemist therefore must modify the compound to reduce or eliminate these undesirable features without losing the desired biological activity. Replacement or modification of functional groups with other groups having similar properties is known as isosteric replacement, or bioisosteric replacement. ... 

Therefore, starting in the 1980s, medicinal chemists discovered that the selective introduction of fluorine into biologically active molecules exercised an influence on activity there are numerous reports of compounds incorporating fluorine as either a bioisosteric replacement for hydrogen or an isoelectronic replacement for the hydroxyl group [ 1,2],... 

The combination of identifying bioisosteric replacements in a lead molecule together with the multiobjective prioritization of virtual molecules in that chemical series for synthesis provides the medicinal chemist with the key information for making design decisions in a therapeutic project. The approaches to identifying these replacements will be covered in Parts Two and Three of this book, but they can all be applied in this challenge. 

Bioisosterism is a key concept in modern medicinal chemistry. This chapter has provided an in-depth overview of the types of classical bioisosteric replacements with real-world exemplars of successful bioisosteric replacements from the literature. 

Devereux, M. and Popelier, P.LA. (2010) In silico techniques for the identification of bioisosteric replacements for drug design. Current Topics in Medicinal Chemistry, 10, 657-668. 

Wassermann, A.M.and Bajorath, J. (2011) Large-scale exploration of bioisosteric replacements on the basis of matched molecular pairs. Future Medicinal Chemistry, 3, 425-436. 

Pragmatic Bioisostere Replacement in Medicinal Chemistry A Software Maker s Viewpoint 219... 

A considerable amount of knowledge has been collated in recent years, in large molecular databases with metadata that can be analyzed and brought to bear in bioisosteric replacement. Knowledge-based methods form the second part, covering experimentally determined bioisosteric replacements from the medicinal chemistry... 

Rescaffolding, bioisosteric replacement, or fragment replacement all describe workflows where a part of a molecule is replaced by another chemical moiety by retaining the biological activity [13]. The aim of this process is the design of molecules with novel IP or different properties. This concept has a long history in medicinal chemistry, but recently this process is heavily supported by methods of computational chemistry. Based on the retrospective evaluation of COX inhibitors, we will discuss this approach in more detail. 

As we have seen in Chapter 15, fluorine plays an important role in medicinal chemistry with almost a quarter of all drugs in the pharmaceutical pipeline containing fluorine. The high electronegativity and small size (approximately equal to ojygen) of fluorine have made it a bioisosteric replacement for either hydrogen or ojygen. It has the ability to modify the pK of amines, alcohols... 

Bioisosterism is now one of the most important tools that medicinal chemists have at their disposal. Through shrewd application of bioisosteres that have experimental precedent or have been identified by theoretical calculations, the medicinal chemist is now well prepared with highly effective tools that have been demonstrated to be of great utility in therapeutic design programs. The remaining chapters in this part will detail the key theories behind bioisosteres and their replacement. 

The discovery and development of a candidate for clinical evaluation is a long process that involves small modifications to a lead compound to improve some of its properties, such as pharmacological activity, selectivity, and pharmacokinetics. This is often achieved by the medicinal chemists by replacing a functional group with groups sharing similar physical or chemical properties and maintaining similar activity, which are defined as bioisosteres. We will hereby provide a historical overview of the development and evolution of the concepts of isosterism and bioisosterism, followed by a selection of successful examples of bioisosteric modifications reported in the literature. 

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