Functional groups bioisosteres

The use of fluorine to modulate properties including potency, selectivity, pharmacokinetics, and toxicity has have been highlighted. Fluorine has also been suggested as a potential bioisosteric replacement for a number of functional groups, examples of which are presented in the final section. 

The local anesthetics can be broadly categorized on the basis of the chemical nature of the linkage contained within the intermediate alkyl chain group. The amide local anesthetics include lidocaine (7.5), mepivacaine (7.6), bupivacaine (7.7), etidocaine (7.8), prilocaine (7.9), and ropivacaine (7.10) the ester local anesthetics include cocaine (7.11), procaine (7.12), benzocaine (7.13), and tetracaine (7.14). Since the pharmacodynamic interaction of both amide and ester local anesthetics with the same Na" channel receptor is essentially idenhcal, the amide and ester functional groups are bioisosterically equivalent. However, amide and ester local anesthetics are not equal from a pharmacokinetic perspective. Since ester links are more susceptible to hydrolysis than amide links. 

Both the ester and N-substituted amide functional groups are bioisosteres (Fig. 20-14), which explains the occurrence of these groups in similar po.sitions in the structures of local ane.sthetics. 

F. The bioisosterism concept F. Reversal of functional groups C. Bioisosteries involving... 

Biologically active molecules containing amide bonds suffer usually of pharmacokinetic liability. In order to increase their stability, bioisosteric transformation of the carboxamide have been performed and yielded a lot of successful examples especially in the area of petidomimetic. The isosteric replacements for peptidic bonds have been summarized by Spatola and by Fauchere. " The most used and well-established modihcations are iV-methylation, configuration change (o-conhguration at Ca), formation of a retroamide or an a-azapeptide, use of aminoisobutyric or dehydroamino acids, replacement of the amidic bond by an ester [depsipeptide], ketomethylene, hydroxyethyl-ene or thioamide functional group, carba replacement of the amidic carbonyl, and use of an olefinic double bond (Figure 15.33). 

Thanks to their ir electron clouds and to their small volume, ethynyl groups can sometimes function as bioisosteres of... 

Importantly, the nonclassical bioisosteres are preeisely the replaeements of functional groups not falling within the regimen by classical definitions. Although, several of these functional moieties practically just behave as one of the following characteristic specific features, such as ... 

The tetrazole functional group is of particular interest in medicinal chemistry, because of its potential role as a bioisostere of the carboxyl group. In this context, Schulz et al. have demonstrated the synthetic utility of the cyano group of arylni-trile boronates as a source of tetrazole derivatives under microwave conditions. The reaction is conducted with azidotrimethylsilane and dibutyltin oxide as catalyst to provide aryltetrazole boronates in yields ranging from 60 to 93% [56]. In the same manner, microwaves may assist successful conversion of sterically hindered nitriles into tetrazoles [57]. 

Functional Group Modification Isosterism and Bioisosterism Isosterism... 

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. ... 

Carboxylic esters are often unstable in vivo consequently many different bioisosteres for this functional group have been tried, most of them being small heterocycles. For a series of CDK2 inhibitors like 4 (Figure 8.10) this problem could be overcome through the use of an... 

Bioisosteres can be used creatively for many other functional groups besides those containing a carbonyl moiety. Figure 8.11 shows two of these. Phenolic groups like the one in the... 

These four key generalized parameters, with specific properties governing the optimization of each, provide what can be formalized as the changes that may be made in lead optimization to provide guidance on the optimization of functional groups that are bioisosteric. 

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. 

The above examples illustrate the sometimes poor permeability observed with amide functional groups in drug compounds and the need to replace them with bioisosteres to overcome these issues. There are other functional groups as well that can lead to poor membrane permeability such as the arginine mimetics, guanidine. 

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