The Development of INT131 as a Selective PPAR Modulator: Approach to a Safer Insulin Sensitizer
Selective PPARγ modulation
separates dose response curves of different PPARγ effects. Left: PPARγ full
agonists activate the range of
receptor responses in a linked fashion. Hence, increasing concentration (or
dose) increases responses in concert. In the clinical setting, higher doses of
TZDs produce greater efficacy as well as greater side effects.
Right: selective PPAR modulation is
response and context-dependent. Depending on the cellular setting and the
response being measured, SPPARM activity may have different potency (top) or
different maximal activity (efficacy, bottom) compared to a full agonist.
Hence, increasing concentration (or dose) may lead to increases in some
responses without linked increases in others. This offers the potential in the
clinical setting for separation of antidiabetic efficacy from side effects such
as edema and weight gain.