T2384, a Novel Antidiabetic Agent with Unique Peroxisome Proliferator-activated Receptor γ Binding Properties

Abstract

The nuclear hormone receptor peroxisome proliferator-activated receptor ␥ (PPAR␥) plays central roles in adipogenesis and glucose homeostasis and is the molecular target for the thiazolidinedione (TZD) class of antidiabetic drugs. Activation of PPAR␥ by TZDs improves insulin sensitivity; however, this is accompanied by the induction of several undesirable side effects. We have identified a novel synthetic PPAR␥ ligand, T2384, to explore the biological activities associated with occupying different regions of the receptor ligand-binding pocket. X-ray crystallography studies revealed that T2384 can adopt two distinct binding modes, which we have termed "U" and "S", interacting with the ligand-binding pocket of PPAR␥ primarily via hydrophobic contacts that are distinct from full agonists. The different binding modes occupied by T2384 induced distinct patterns of coregulatory protein interaction with PPAR␥ in vitro and displayed unique receptor function in cell-based activity assays. We speculate that these unique biochemical and cellular activities may be responsible for the novel in vivo profile observed in animals treated systemically with T2384. When administered to diabetic KKAy mice, T2384 rapidly improved insulin sensitivity in the absence of weight gain, hemodilution, and anemia characteristics of treatment with rosiglitazone (a TZD). Moreover, upon coadministration with rosiglitazone, T2384 was able to antagonize the side effects induced by rosiglitazone treatment alone while retaining robust effects on glucose disposal. These results are consistent with the hypothesis that interactions between ligands and specific regions of the receptor ligand-binding pocket might selectively trigger a subset of receptor-mediated biological responses leading to the improvement of insulin sensitivity, without eliciting less desirable responses associated with full activation of the receptor. We suggest that T2384 may represent a prototype for a novel class of PPAR␥ ligand and, furthermore, that molecules sharing some of these properties would be useful for treatment of type 2 diabetes.

Covalent Peroxisome Proliferator-activated Receptor γ Adduction by Nitro-fatty Acids

“…However, full PPAR␥ agonists also stimulate adipocyte differentiation in vitro and induce weight gain in vivo, motivating a search for selective modulators that activate a subset of PPAR␥-regulated genes with reduced side effects (7,35). Here, we reveal that electrophilic NO 2 -FA derivatives, products of the oxidizing and nitrating conditions promoted by inflammation, bind to and react avidly with the redox-sensitive LBD Cys-285 of PPAR␥ (Fig.…”

Selective PPARγ modulator INT131 normalizes insulin signaling defects and improves bone mass in diet-induced obese mice

“…However, there is accumulating evidence that undesirable side effects, including body weight gain, anemia, fluid retention, and congestive heart failure, were seen in type 2 diabetic patients or animals treated with these compounds (13,16,27). Recent studies have developed a number of selective peroxisome proliferator-activated receptor modulators, including T2384, FK614, and PAR-1622, all of which are partial PPAR␥ agonists (23,30,31). The beneficiary effect of these insulinsensitizing compounds is that antihyperglycemic activity occurred independently of typical side effects in diabetic animals (14).…”

Pharmacology and in Vitro Profiling of a Novel Peroxisome Proliferator-Activated Receptor .GAMMA. Ligand, Cerco-A

“…Recently a number of PPARg modulators were reported (PAR1622, 14) FK614, [15][16][17][18][19][20] SPPARMgM5, 21) INT131, 22,23) T2384, 24) and MBX-102, 25,26) etc.). They showed profiles of the PPARg partial agonists in vitro and demonstrated attenuating side effects in vivo compared to the currently marketed PPARg agonists.…”

“…13) Many pharmaceutical companies are attempting to develop safer PPARg ligands, including selective PPARg partial agonists, and some of these were reported previously. [14][15][16][17][18][19][20][21][22][23][24][25][26] The potency and safety of most of those compounds have not been well characterized in vivo compared to the currently marketed PPARg agonist.…”