Bioisostere approach

Gustavsson A.-L., Tuvesson M., Larsson M. C., Wenqi W., Hansson B. S. and Liljefors T. (1997) Bioisosteric approach to elucidation of binding of the acetate group of a moth pheromone component to its receptor. J. Chem. Ecol. 23, 2755-2776. 

No two substituents are exactly alike. Any substitution impacts size, shape, electronic distribution, lipophilicity, pKa, chemical reactivity, susceptibility to metabolism, and the like. The bioisosteric approach is the total change induced by substituent replacement on the potency, selectivity, duration of action, bioavailability and toxicity, of an agrochemical. The following groups are examples of... 

Lanter, J.C., Fiordeliso, J.J., Allan, G.F., Musto, A., Hahn do, W. and Sui, Z. (2006) A bioisosteric approach to the discovery of indole carhinol androgen receptor ligands. Bioorganic et Medicinal Chemistry Letters, 16, 5646-5649. 

The simplest application of the bioisostere approach to build in structural novelty would probably lie in the substitution of a single atom by one not covered in existing patents, although changes this small run the risk of being considered obvious by patent examiners. 

Aminoheterocycle bioisosteric approaches to amide groupings are exemplified in a report on soluble epoxide hydrolase inhibitors [5j. The replacement of the amide grouping in 1 by adoption of the tethering strategy of linking the carbonyl to adjacent side chains or benzene rings produced 2 (Figure 3.2). 

AP, that result from the application of particular transformations, AS, and hence provide an inverse quantitative structure-activity relationship (QSAR) approach to lead optimization [19]. Another difference is that, given an appropriate source of data, they can model not only biological activity, the principal focus of the bioisosterism approaches, but also any chemical, physicochemical, or ADMETproperty that needs to be optimized. 

Patani G A and E J LaVoie 1996. Bioisosterism A Rational Approach in Drug Design. Chemical Reviei 96 3147-3176. 

In a series of reports on their class of DPPIV inhibitors [27-29], workers from Merck have shown that the incorporation of an acid moiety (or related bioisostere) into an amine-containing template to furnish a zwitterionic system has been ofuse in minimizing hERG activity. For example, incorporation of an acid bioisostere into the biaryl P-methylphenylalanine template has been shown to afford enhancements in selectivity over hERG (cf. compounds 40 and 41) [29]. A concomitant reduction in oral bioavailability was observed between the two compounds, which underlines the main limitation in this approach. 

The oldest example of the use of nonclassical isosteres involves the replacement of the carboxamide in foUc acid by sulfonamide, to give the sulfanilamides. Diaminopyrimidines, as antimalarial agents, are also based on folate isosterism, in addition to the exploitation of auxiliary binding sites on dihydrofolate reductase. This concept of nonclassical isosteres or bioisosteres — that is, moieties that do not have the same nnmber of atoms or identical electron structure — is really the classical structure modification approach. 

Note broadly similar biological properties. Bioisosteric replacement must allow a number of properties to remain, and some to be altered. Thus, one may allow selective binding to a receptor to remain, but alter an agonist to an antagonist. This is the classical approach to many drugs that was pursued long before the term bioisostere was invented. 

Bioisosteric substitutions are a commonly used strategy in medicinal chemistry drug design as an approach to enhance the desired biological or physical... 

Using microdialysis experiments the relative oral bioavailabilities of the compounds 34, 35, 11, 80, 12, 83 and 9 could be calculated. These data show that a compound with a catechol or a phenol possesses a low relative oral bioavailability (compounds 11, 80, 12 and 9). To circumvent such a low relative oral bioavailability a bioisostere of a phenol could be introduced or a prodrug approach could be applied. Compounds 34 and 35 are examples of a bioisosteric replacements and compound 83 is a prodrug of a catecholic or a phenolic 2-aminotetralin. Both types of compounds show an improved relative oral bioavailability, as compared to the... 

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