Lead optimization peptidomimetics

Recent examples of successful peptide-ligand based discoveries of drug-like peptidomimetics include the discovery of SST antagonists, or the discovery of non-peptidic antagonists of the recently deorphanized urotensin II receptor at Sanofi-Aventis. ° As illustrated in Fig. 3, Flohr etal. used 3D models of the NMR solution structure of cyclic peptide derivatives of Urotensin II as a template for virtual 3D pharmacophore searches which resulted into non-peptidic candidates for lead optimization. 

The third group of alliances focuses on lead optimization. Here, a particular lead is known, such as a small peptide and it is desired to optimize the activity of that lead. In the case of peptides this could be accomplished through phage display and/or peptidomimetic combinatorial chemistry. Companies involved in alliances of this type have proprietary technologies that enable them to generate usually small-molecule libraries built around particular molecular themes, for example, steroid cores. Examples include alliances of Ontogen, Dyax, ArQule, etc. 

Aqueous solubility, potency, and permeability are three factors under medicinal chemistry control that must be optimized to achieve a compound with acceptable oral absorption. Typically a lead (chemistry starting point) is deficient in all three parameters. The interrelationships of these three parameters has been described in a series of publications from Pfizer researchers. Figure 16.1 provides a bar graph that depicts minimum acceptable solubility as a function of projected clinical potency and intestinal permeability. A minimum thermodynamic aqueous solubility of 52 j,g/mL is required in the most commonly encountered situation where the projected clinical potency is Img/kg and the permeability is in the average range. If the permeability is in the lower tenth percentile as might be found for a peptidomimetic the minimum acceptable solubility is... 

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