INT-131, a PPARgamma agonist for the treatment of type 2 diabetes.

INT-131, a novel, non-thiazolidinedione (TZD), selective peroxisome proliferator-activated receptor (PPAR)gamma modulator, is in development by InteKrin Therapeutics Inc for the treatment of type 2 diabetes mellitus (non-insulin dependent diabetes). The concept of selective modulation involves targeting and activating specific genes to minimize side effects while maintaining therapeutic benefits. In vitro, INT-131 attenuated adipogenic properties, indicating moderate PPARgamma activation/cofactor recruitment compared with the full agonistic properties of TZD compounds. INT-131 also compared favorably with TZDs in 6-month toxicity studies in rats and monkeys, exhibiting no increases in body or organ weights, and no relevant observations of edema or other fluid retention, which has been associated with congestive heart failure in TZDs. In phase I and II clinical trials, INT-131 was well tolerated, without any serious adverse events or reports of fluid retention. Antidiabetic efficacy was comparable with TZDs and was moderately greater than for other new, oral antidiabetic drugs, although only fasting plasma glucose levels were recorded. INT-131 appears to be a promising new PPARgamma agonist with potent antidiabetic actions and a favorable side effect profile; however, additional, extensive clinical investigation is required to justify the non-inferiority of this compound to TZDs and other oral antidiabetic drugs.