Functionalization of fatty acid mimetics for solid-phase coupling and subsequent target identification.

Fatty acid mimetics such as pirinixic acid (PA) derivatives and 2-(phenylthio)alkanoic acid derivatives are drug-like small molecules with an interesting pharmacological profile. Previously, we have characterized PA derivatives (e.g., 1) as dual agonists of peroxisome proliferator-activated receptors (PPARs) α and γ and as inhibitors of microsomal prostaglandin E(2)-synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO). 2-(Phenylthio)alkanoic acids (e.g., 2) were shown to act as highly active and selective PPARα agonists. Encouraged by these results, we would like to identify other target proteins and, thereby, further explore the pharmacological profile of these molecules. An elegant method to screen for potential interaction partners is the so-called "protein-fishing" approach. Requirement is coupling of a functionalized small molecule to a solid phase which is used for biological experiments. Ideally, the pharmacophore of the small molecule remains intact as far as possible. Here, we describe the successful design and synthesis of functionalized fatty acid mimetics, thus providing an eligible starting point for solid-phase coupling and subsequent "protein-fishing" experiments.