Lead optimization isosteres

Showell, G. A., Mills, J. S. Chemistry challenges in lead optimization silicon isosteres in drug discovery. Drug Disc. Today 2003, S(12), 551-556. 

Fig. 15 Map of isosterical replacement for lead optimization of natural strobirulin A...

In a general manner, medicinal chemists should take into account the use of the twin drug approach as soon as they get a lead compound that need to be optimized. Dimerization of a lead or association of two different pharmacophores must be considered during the primary exploration of SARs as well as isosteric replacement, homology and conformational restriction are used during this process. 

The design of enzyme inhibitors has included random screening of synthetic chemical agents, natural products, and combinatorial libraries followed by molecular optimization or structure-activity relationships of so-called lead structures as well as bio-isosteric analogues of the enzyme substrates themselves. Drugs (e.g., finasteride) also have been developed for one indication but, based on observed side effects, have lead to other uses. 

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