CVT-4325: a potent fatty acid oxidation inhibitor with favorable oral bioavailability

Elzein, Elfatih; Ibrahim, Prabha; Koltun, Dmitry O.; Rehder, Ken S.; Shenk, Kevin D.; Marquart, Timothy A.; Jiang, Bob; Li, Xiaofen; Natero, Reina; Li, Yuan; Nguyen, Marie L.; Kerwar, S.S.; Chu, Nancy; Soohoo, Daniel; Hao, Jia; Maydanik, Victoria Y; Lustig, David A.; Zeng, Dewan; Leung, Kwan; Zablocki, Jeff

doi:10.1016/j.bmcl.2004.09.077

Cited by 29 publications

(14 citation statements)

References 14 publications

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“…Nevertheless, these findings are in keeping with the reported effects of this piperazine derivative on fatty acid and glucose oxidation in rat hearts [18]. CVT-4325 which inhibits 1-14[c] palmiyoyl CoA oxidation in rat heart mitochondria [17], was found to inhibit fatty acid oxidation and concurrently increase glucose oxidation with potencies in the range of 0.9 to 10.9 mM with a greater potency when the hearts were perfused with 1.2 mM palmitate [18]. Theoretically, FFA oxidation requires 11% more oxygen consumption for a given amount of ATP synthesis than glucose or lactate [30].…”

Section: Discussionsupporting

confidence: 90%

“…The purpose of the present study was to evaluate the effects of acute treatment with a novel inhibitor of myocardial fatty acid oxidation on LV function and MVO 2 . CVT-4325 is a potent piperazine derivative shown to inhibit, in a concentration-dependent manner, fatty acid oxidation in cardiac mitochondria and in the rat isolated perfused heart with potencies (IC50 values) of 490 nM and 0.9 mM (palmitate=1.2 mM), respectively [17,18]. In the present study, we tested the hemodynamic and metabolic effects of an acute intravenous infusion of CVT-4325 in dogs with HF (LV ejection fraction, EFe35%).…”

Section: Introductionmentioning

confidence: 98%

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CVT-4325 Inhibits Myocardial Fatty Acid Uptake and Improves Left Ventricular Systolic Function without Increasing Myocardial Oxygen Consumption in Dogs with Chronic Heart Failure

Imai

Rastogi

Sharma

et al. 2006

Cardiovasc Drugs Ther

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 98%

CVT-4325 Inhibits Myocardial Fatty Acid Uptake and Improves Left Ventricular Systolic Function without Increasing Myocardial Oxygen Consumption in Dogs with Chronic Heart Failure

Imai

Rastogi

Sharma

et al. 2006

Cardiovasc Drugs Ther

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“…In addition, the fatty acid oxidation inhibitor CVT-4325 30 enhanced killing of CLL cells by DEX ( Figure 6C, right upper panel). Combination indices for these inhibitors with DEX were ,1 ( Figure 6C, lower panels), indicating synergy.…”

Section: Ppara and Fatty Acid Oxidation Mediate Gc Resistancementioning

confidence: 99%

PPARα and fatty acid oxidation mediate glucocorticoid resistance in chronic lymphocytic leukemia

Tung

Shi

Wong

et al. 2013

Blood

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Key Points• Glucocorticoids downregulate PKM2 and metabolism in CLL cells, impairing access to bioenergetic programs needed to repair cell damage.• PPARa and fatty acid oxidation antagonists potentiate the cytotoxic effects of glucocorticoids.High-dose glucocorticoids (GCs) can be a useful treatment for aggressive forms of chronic lymphocytic leukemia (CLL). However, their mechanism of action is not well understood, and resistance to GCs is inevitable. In a minimal, serum-free culture system, the synthetic GC dexamethasone (DEX) was found to decrease the metabolic activity of CLL cells, indicated by down-regulation of pyruvate kinase M2 (PKM2) expression and activity, decreased levels of pyruvate and its metabolites, and loss of mitochondrial membrane potential. This metabolic restriction was associated with decreased size and death of some of the tumor cells in the population. Concomitant plasma membrane damage increased killing of CLL cells by DEX. However, the nuclear receptor peroxisome proliferator activated receptor a (PPARa), which regulates fatty acid oxidation, was also increased by DEX, and adipocyte-derived lipids, lipoproteins, and propionic acid protected CLL cells from DEX. PPARa and fatty acid oxidation enzyme inhibitors increased DEX-mediated killing of CLL cells in vitro and clearance of CLL xenografts in vivo. These findings suggest that GCs prevent tumor cells from generating the energy needed to repair membrane damage, fatty acid oxidation is a mechanism of resistance to GC-mediated cytotoxicity, and PPARa inhibition is a strategy to improve the therapeutic efficacy of GCs. (Blood. 2013;122(6):969-980)

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“…Radioisotopes were obtained from PerkinElmer Life and Analytical Sciences (Boston, MA), and 13 C-labeled substrates were from Cambridge Isotope Laboratories (Andover, MA). Ranolazine and CVT-4325 were obtained from the bioorganic chemistry group at CV Therapeutics (Palo Alto, CA); the structures of these drugs have been reported previously (McCormack et al, 1998;Elzein et al, 2004). Both drugs were prepared as stock solutions of 10 and 3 mM, respectively, in DMSO.…”

Section: Methodsmentioning

confidence: 99%

A Comparison between Ranolazine and CVT-4325, a Novel Inhibitor of Fatty Acid Oxidation, on Cardiac Metabolism and Left Ventricular Function in Rat Isolated Perfused Heart during Ischemia and Reperfusion

Wang

Fraser²,

Lloyd³

et al. 2007

J Pharmacol Exp Ther

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Inhibition of fatty acid oxidation has been reported to be cardioprotective against myocardial ischemic injury; however, recent studies have questioned whether the cardioprotection associated with putative fatty acid oxidation inhibitors, such as ranolazine and trimetazidine, are due to changes in substrate oxidation. Therefore, the goals of this study were to compare the effects of ranolazine with a new fatty acid oxidation inhibitor, CVT-4325, on carbohydrate and fatty acid oxidation and on left ventricular (LV) function in the response to ischemia/reperfusion in rat isolated perfused hearts. Metabolic fluxes were determined in hearts perfused in an isovolumic Langendorff mode using 13 C nuclear magnetic resonance isotopomer analysis or in isolated working hearts using [14 C]glucose and [3 H]palmitate, with and without 10 M ranolazine or 3 M CVT-4325. Isovolumic perfused hearts were also subjected to 30 min of low-flow ischemia (0.3 ml/min) and 60 min of reperfusion, and working hearts were subjected to 15 min of zero-flow ischemia and 60 min of reperfusion. Regardless of the experimental protocol, ranolazine had no effect on carbohydrate or fatty acid oxidation, whereas CVT-4325 significantly reduced fatty acid oxidation up to ϳ7-fold with a concomitant increase in carbohydrate oxidation. At these same concentrations, although ranolazine significantly improved LV functional recovery following ischemia/reperfusion, CVT-4325 had no significant protective effect. These results demonstrate that at pharmacologically relevant concentrations, ischemic protection by ranolazine was not mediated by inhibition of fatty acid oxidation and conversely that inhibition of fatty acid oxidation with CVT-4325 was not associated with improved LV functional recovery.

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CVT-4325: a potent fatty acid oxidation inhibitor with favorable oral bioavailability

Cited by 29 publications

References 14 publications

CVT-4325 Inhibits Myocardial Fatty Acid Uptake and Improves Left Ventricular Systolic Function without Increasing Myocardial Oxygen Consumption in Dogs with Chronic Heart Failure

CVT-4325 Inhibits Myocardial Fatty Acid Uptake and Improves Left Ventricular Systolic Function without Increasing Myocardial Oxygen Consumption in Dogs with Chronic Heart Failure

PPARα and fatty acid oxidation mediate glucocorticoid resistance in chronic lymphocytic leukemia

A Comparison between Ranolazine and CVT-4325, a Novel Inhibitor of Fatty Acid Oxidation, on Cardiac Metabolism and Left Ventricular Function in Rat Isolated Perfused Heart during Ischemia and Reperfusion

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