Disease relevance of CP 72466

• We compared the effect of CP 68722 with the sulfonylureas, the primary drugs used in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) [1].
• Antidiabetic agent englitazone enhances insulin action in nondiabetic rats without producing hypoglycemia [2].
• The two compounds that were selected as development candidates (englitazone and darglitazone) did not produce cataracts in rats exposed daily for 3 months [3].

High impact information on CP 72466

• Although englitazone alone did not activate PI 3-kinase, it did enhance the stimulation of the enzyme produced by a submaximally effective insulin concentration [4].
• Englitazone did not affect the expression of the peroxisome proliferator response element-containing fatty acyl CoA synthase gene, although it cannot be ruled out that expression of other lipogenic enzymes are altered by englitazone via peroxisome proliferator activated receptor-gamma activation or by an alternate pathway [4].
• Significant (63%) inhibition of insulin-stimulated lipogenesis occurred at a concentration of englitazone (30 micromol/l) that did not affect MAPK activation, which suggests that the drug's inhibitory effect on lipogenesis is not mediated by this pathway [4].
• However, englitazone inhibits insulin-stimulated lipogenesis without inhibiting PI 3-kinase activity [4].
• The aim of this study was to compare the effects of insulin and the insulinomimetic agent, englitazone, on functional end points and putative mediators of insulin action in 3T3-L1 adipocytes [4].

Biological context of CP 72466

• In addition, englitazone decreased insulin-stimulated lipogenesis in a concentration-dependent manner [4].
• Treatment of ob/ob mice with 50 mg/kg englitazone reversed the defects in insulin-stimulated glycolysis (from [3-3H]glucose) and glycogenesis and basal glucose oxidation (from [1-14C]glucose) in isolated soleus muscles [5].
• 4. Englitazone also inhibited Ca(2+)-activated non-selective cation (NSCa) channels in inside-out patches in a concentration-dependent and voltage-independent manner with an IC50 value of 10 microM [6].
• In isolated perfused rat livers of 24-hr fasted rats infused with lactate (2 mM), englitazone (6.25 to 50 microM) produced a concentration-dependent decrease (32-93%) in hepatic gluconeogenesis [7].
• We studied the efficacy of two of these agents, pioglitazone and englitazone, in preventing glucocorticoid-induced insulin resistance in rats, and examined the potential role of changes in GLUT4 expression in their action in skeletal muscle [8].

Anatomical context of CP 72466

• Insulinlike activity of new antidiabetic agent CP 68722 in 3T3-L1 adipocytes [1].
• The stimulation of uptake by CP 68722 or insulin could be prevented by incubating the cells at 10 degrees C, a temperature that impedes translocation of glucose transporters to the plasma membrane [1].
• Effect of englitazone on KATP and calcium-activated non-selective cation channels in CRI-G1 insulin-secreting cells [6].
• Single channel currents recorded from inside-out patches excised from oocytes expressing Kir6.2-SUR1 currents were inhibited by tolbutamide, Mg-ATP, englitazone and ciclazindol, in the absence of azide, with potencies similar to native K(ATP) channels [9].
• Actions of the novel antidiabetic agent englitazone in rat hepatocytes [10].

Associations of CP 72466 with other chemical compounds

• 3. Application of englitazone produced a concentration-dependent inhibition of K(ATP) currents activated by diazoxide (200 microM) with an IC50 value of 7.7 microM and a Hill coefficient of 0.87 [11].
• In the presence of azide, Kir6.2-SUR1 currents were inhibited by englitazone and tolbutamide but not ciclazindol [9].
• Comparative effects of englitazone and glyburide on gluconeogenesis and glycolysis in the isolated perfused rat liver [7].
• Whereas dexamethasone treatment alone increased GLUT4 protein content in rat soleus muscle by 25%, additional treatment with pioglitazone or englitazone did not further significantly alter GLUT4 levels [8].

Gene context of CP 72466

• Englitazone did not reverse this decrease in IRS-1 and PI-3-kinase levels in fat from high-fat-fed rats (there was a further 25-30% decrease, P < 0.05), nor did it increase PI-3-kinase activity in 3T3-L1 adipocytes under conditions (48 h incubation) where it stimulated 2-DG uptake sixfold or enhanced insulin-stimulated 2-DG uptake [12].
• It is likely that ciclazindol and englitazone inhibit K(ATP) currents by interaction with the Kir6.2 subunit [9].
• Single channel currents derived from Kir6.2Delta26, expressed in HEK 293 cells, were inhibited by ciclazindol and englitazone irrespective of the absence or presence of SUR1 [9].
• The englitazone concentration inhibition curve in the presence of leptin resulted in an IC50 value and Hill coefficient of 52 microM and 3.2, respectively [11].

Analytical, diagnostic and therapeutic context of CP 72466

• 5. In whole-cell recordings englitazone, at a relatively high concentration (50 microM) in comparison with that required to block KATP and NSCa channels, inhibited voltage-activated Ca2+ currents by 33% but did not inhibit voltage-activated K+ and Na+ currents [6].

References