Activation of PPAR subtypes offers a promising strategy for the treatment of diabetes mellitus and some of its risk factors. Herein, we report a systematic description of the SAR of 168 compounds screened against the three PPAR subtypes using the principles of activity landscape modeling. We employed consensus dual-activity difference maps recently reported. The analysis is based on pairwise relationships of potency difference and structure-similarity, which was calculated from the combination of four different 2D and 3D fingerprints. Dual-activity difference maps uncovered regions in the landscape with similar SAR as well as regions with inverse SAR. Analysis of pairs of compounds with high structure similarity revealed the presence of single-, dual-, and 'pan-receptor' activity cliffs. Single-, dual-, and pan-receptor scaffold hops are also discussed. The analysis of the chemical structures of selected data points suggests specific structural features that are helpful for the design of new PPAR agonists.

Activity landscape modeling of PPAR ligands with dual-activity difference maps

244th National Meeting (2012)

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