Bioisosterism: a useful strategy for molecular modification and drug design.

This review aim to demonstrate the role of bioisosterism in rational drug design as well as in the molecular modification and optimization process aiming to improve pharmacodynamic and pharmacokinetic properties of lead compounds. Bioisosterism is a strategy of Medicinal Chemistry for the rational design of new drugs, applied with a lead compound (LC) as a special process of molecular modification (1). The LC should be of a completely well known chemical structure and possess an equally well known mechanism of action, if possible at the level of topographic interaction with the receptor, including knowledge of all of its pharmacophoric group. Furthermore, the pathways of metabolic inactivation (2), as well as the main determining structural factors of the physicochemical properties which regulate the bioavailability, and its side effects, whether directly or not, should be known so as to allow for a broad prediction of the definition of the bioisosteric relation to be used. The success of this strategy in developing new substances which are therapeutically attractive has observed a significant growth in distinct therapeutic classes, being amply used by the pharmaceutical industry to discover new analogs of therapeutic innovations commercially attractive (me-too), and also as a tool useful in the molecular modification. There may be innumerous reasons for the use of bioisosterism to design new drugs, including the necessity to improve pharmacological activity, gain selectivity for a determined receptor or enzymatic isoform subtype - with simultaneous reduction of certain adverse effects -, or even optimize the pharmacokinetics the LC might present. In this paper, we will discuss bioisosterism as a strategy of molecular modification, showing its importance in building a new series of congeners compounds designed as candidate of new drugs, giving examples of successful cases in distinct therapeutic classes (3-7).