int-131 and Diabetes-Mellitus--Type-2

The thiazolidinediones (TZDs) rosiglitazone and pioglitazone improve glucose homeostasis through activation of peroxisome proliferator-activated receptor (PPAR)-γ. Their use, however, has been limited due to adverse effects that include body weight gain and edema leading to congestive heart failure. Selective PPAR-γ modulators (SPPARMs) are second generation PPAR-γ ligands designed to improve insulin sensitivity with minimal undesirable effects associated with first generation PPAR-γ agonists. INT131 is one of the first SPPARMs to reach human trials. Early phase human studies with INT131 look promising with changes in plasma lipids and glucose being equal or better than what is seen with rosiglitazone and pioglitazone treatment but without evidence of edema. This profile of improved glucose homeostasis, improved plasma lipids, and reduced inflammation in the absence of edema would be expected to reduce cardiovascular risk in patients with Type 2 diabetes mellitus. Recent patents of novel approaches for the use of PPAR-γ related compounds with the potential for this improved risk-benefit ratio are discussed.

Topics: Animals; Cardiovascular Diseases; Clinical Trials, Phase II as Topic; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Humans; Insulin Resistance; PPAR gamma; Quinolines; Sulfonamides

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a clinically validated target for treatment of insulin resistance. PPARgamma activation by full agonists such as thiazolidinediones has shown potent and durable glucose-lowering activity in patients with type 2 diabetes without the concern for hypoglycemia or gastrointestinal toxicities associated with some other medications used to treat this disease. However, thiazolidinediones are linked to safety and tolerability issues such as weight gain, fluid retention, edema, congestive heart failure, and bone fracture. Distinctive properties of PPARgamma provide the opportunity for selective modulation of the receptor such that desirable therapeutic effects may be attained without the unwanted effects of full activation. PPARgamma is a nuclear receptor that forms a complex with coreceptor RXR and a cell type- and cell state-specific array of coregulators to control gene transcription. PPARgamma affinity for these components, and hence transcriptional response, is determined by the conformational changes induced by ligand binding within a complex pocket with multiple interaction points. This molecular mechanism thereby offers the opportunity for selective modulation. A desirable selective PPARgamma modulator profile would include high-affinity interaction with the PPARgamma-binding pocket in a manner that leads to retention of the insulin-sensitizing activity that is characteristic of full agonists as well as mitigation of the effects leading to increased adiposity, fluid retention, congestive heart failure, and bone fracture. Examples of endogenous and synthetic selective PPARgamma modulator (SPPARM) ligands have been identified. SPPARM drug candidates are being tested clinically and provide support for this strategy.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Gluconeogenesis; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin Resistance; Pioglitazone; PPAR gamma; Quinolines; Retinoid X Receptors; Rosiglitazone; Sulfonamides; Thiazolidinediones

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.

Topics: Administration, Oral; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Patents as Topic; PPAR gamma; Quinolines; Sulfonamides; Treatment Outcome

INT131 besylate is a potent, nonthiazolidinedione, selective peroxisome proliferator-activated receptor γ (PPARγ) modulator (SPPARM) designed to improve glucose metabolism while minimizing the side effects of full PPARγ agonists. This placebo-controlled study compared the efficacy and side effects of INT131 besylate versus 45 mg pioglitazone HCl in subjects with type 2 diabetes (T2D).. This was a 24-week randomized, double-blind, placebo- and active-controlled study of 0.5-3.0 mg INT131 versus 45 mg pioglitazone or placebo daily in 367 subjects with T2D on sulfonylurea or sulfonylurea plus metformin. The primary efficacy analysis was the comparison of change from baseline to week 24 in hemoglobin A1c (HbA1c) across treatment groups. Fluid status was assessed with a prospective scoring system for lower-extremity pitting edema.. INT131 had a steep dose response for efficacy as measured by changes in HbA1c. After 24 weeks' treatment, the 0.5-mg dose demonstrated minimal efficacy (HbA1c -0.3 ± 0.12%) and the 2-mg dose demonstrated near-maximal efficacy (HbA1c -1.1 ± 0.12%), which was not statistically different from the efficacy of 45 mg pioglitazone (HbA1c -0.9 ± 0.12%; P < 0.01 for noninferiority). With the 1-mg dose, INT131 provided significant improvements in glycemic control (HbA1c 0.8 ± 0.12; P < 0.001 vs. placebo) but with less edema, weight gain, and hemodilution than observed with 45 mg pioglitazone.. INT131 demonstrated dose-dependent reductions in HbA1c, equivalent to 45 mg pioglitazone, but with less fluid accumulation and weight gain, consistent with its SPPARM design.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Pioglitazone; PPAR gamma; Prospective Studies; Quinolines; Sulfonamides; Sulfonylurea Compounds; Thiazolidinediones; Treatment Outcome; Weight Gain

INT131 is a potent non-thiazolidinedione (TZD)-selective peroxisome proliferator-activated receptor-γ modulator being developed for the treatment of type 2 diabetes. In preclinical studies and a phase II clinical trial, INT131 has been shown to lower glucose levels and ameliorate insulin resistance without typical TZD side effects. To determine whether the insulin-sensitizing action of INT131 is mediated by effects on insulin-mediated glucose homeostasis and insulin signaling, high-fat diet-induced obese (DIO) insulin-resistant mice treated with INT131 were studied. INT131's effects on bone density were also investigated. Treatment with INT131 enhanced systemic insulin sensitivity, as revealed by lower insulin levels in the fasted state and an increase in the area above the curve during an insulin tolerance test. These effects were independent of changes in adiposity. Insulin-stimulated PI3K activity in skeletal muscle and adipose tissue of DIO mice was significantly reduced ∼50-65%, but this was restored completely by INT131 therapy. The INT131 effects on PI3K activity are most likely due to increased IRS-1 tyrosine phosphorylation. Concurrently, insulin-mediated Akt phosphorylation also increased after INT131 treatment in DIO mice. Importantly, INT131 therapy caused a significant increase in bone mineral density without alteration in circulating osteocalcin in these mice. These data suggest that a newly developed insulin-sensitizing agent, INT131, normalizes obesity-related defects in insulin action on PI3K signaling in insulin target tissues by a mechanism involved in glycemic control. If these data are confirmed in humans, INT131 could be used for treating type 2 diabetes without loss in bone mass.

Topics: Adipose Tissue, White; Animals; Anti-Obesity Agents; Bone Density; Bone Density Conservation Agents; Diabetes Mellitus, Type 2; Diet, High-Fat; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Muscle, Skeletal; Obesity; Phosphatidylinositol 3-Kinases; PPAR gamma; Quinolines; Random Allocation; Signal Transduction; Sulfonamides