The Place of the Bioisosteric Sila-Substitution in Drug Design

Drug design is a complex process that requires a good command of several disciplines including organic and physical chemistry, biochemistry and metabolism, pharmacology, pharmacodynamics and pharmacokinetics. The process starts with the synthesis of compound libraries and their evaluation toward pharmacological targets for biological activity. This first step allows to identify lead compounds characterized by a desired pharmacological activity. However, such identified compounds may have undesirable characteristics that limit their bioavailability, structural features that adversely alter their metabolism, display toxicity or possess unwanted side effects. Converting a pharmacological lead into a successful drug constitutes a major challenge for pharmaceutical laboratories. Among the approaches used to transform lead compounds into safer and clinically relevant agents, the bioisosteric substitution constitutes a key tool at the medicinal chemist disposal. Classical bioisosteres have similar steric and electronic characteristics and have the same number of atoms than the element or substituent for which they are used as a replacement. One of the most common classical bioisosteric substitution is the incorporation of fluorine into a compound in replacement of specific hydroxyl groups or hydrogens atoms. A less well-known classical bioisostere is the replacement of a carbon by a silicon atom (silasubstitution). The silicon bioisostere offers interesting benefits in drug design. The altered bond length and angles of silicon over carbon in a new chemical entity can lead to its improved pharmacological potency, modify its selectivity toward a given target, or change its metabolic rate, respectively. The sila-substitution can also increase the lipophilicity of a compound and hence increase its tissue distribution, particularly through membranes including the blood brain barrier, although with the limitation of a decreased water solubility. This review will present the synthetic methods currently available to effect a sila-substitution, along with its advantages and limitations in drug design. The discussion will be extended to practical examples of compounds currently in clinical trials. Keywords: silicon-carbon substitution, drug design, drug discovery, sila-substitution, silicon bioisostere, silicon chemistry