CVT-4325: a potent fatty acid oxidation inhibitor with favorable oral bioavailability (original) (raw)
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Novel inhibitors of fatty acid oxidation as potential metabolic modulators
Bioorganic & Medicinal Chemistry Letters, 2004
We describe the synthesis of novel inhibitors of fatty acid oxidation as potential metabolic modulators for the treatment of stable angina. Replacement of the 2H-benzo[d]1,3-dioxolene ring system in our initial lead 3 with different benzthiazoles, benzoxazoles and introducing small alkyl substituents into the piperazine ring resulted in analogues with enhanced inhibitory activity against 1-14 [C]-palmitoyl-CoA oxidation in isolated rat heart mitochondria (6, IC 50 =70 nM; 25, IC 50 =23 nM).
Cell Death and Differentiation, 2005
Recent studies suggest a close relationship between cell metabolism and apoptosis. We have evaluated changes in lipid metabolism on permeabilized hepatocytes treated with truncated Bid (tBid) in the presence of caspase inhibitors and exogenous cytochrome c. The measurement of b-oxidation flux by labeled palmitate demonstrates that tBid inhibits b-oxidation, thereby resulting in the accumulation of palmitoyl-coenzyme A (CoA) and depletion of acetyl-carnitine and acylcarnitines, which is pathognomonic for inhibition of carnitine palmitoyltransferase-1 (CPT-1). We also show that tBid decreases CPT-1 activity by a mechanism independent of both malonyl-CoA, the key inhibitory molecule of CPT-1, and Bak and/or Bax, but dependent on cardiolipin decrease. Overexpression of Bcl-2, which is able to interact with CPT-1, counteracts the effects exerted by tBid on b-oxidation. The unexpected role of tBid in the regulation of lipid b-oxidation suggests a model in which tBid-induced metabolic decline leads to the accumulation of toxic lipid metabolites such as palmitoyl-CoA, which might become participants in the apoptotic pathway.
The Journal of Physiology, 2005
has been postulated to be a specific inhibitor of mitochondrial ATP-sensitive K + (K ATP ) channels. However, recent work has shown that 5-HD is activated to 5-hydroxydecanoyl-CoA (5-HD-CoA), which is a substrate for the first step of β-oxidation. We have now analysed the complete β-oxidation of 5-HD-CoA using specially synthesised (and purified) substrates and enzymes, as well as isolated rat liver and heart mitochondria, and compared it with the metabolism of the physiological substrate decanoyl-CoA. At the second step of β-oxidation, catalysed by enoyl-CoA hydratase, enzyme kinetics were similar using either decenoyl-CoA or 5-hydroxydecenoyl-CoA as substrate. The last two steps were investigated using l-3-hydroxyacyl-CoA dehydrogenase (HAD) coupled to 3-ketoacyl-CoA thiolase. V max for the metabolite of 5-HD (3,5-dihydroxydecanoyl-CoA) was fivefold slower than for the corresponding metabolite of decanoate (L-3-hydroxydecanoyl-CoA). The slower kinetics were not due to accumulation of D-3-hydroxyoctanoyl-CoA since this enantiomer did not inhibit HAD. Molecular modelling of HAD complexed with 3,5-dihydroxydecanoyl-CoA suggested that the 5-hydroxyl group could decrease HAD turnover rate by interacting with critical side chains. Consistent with the kinetic data, 5-hydroxydecanoyl-CoA alone acted as a weak substrate in isolated mitochondria, whereas addition of 100 µM 5-HD-CoA inhibited the metabolism of decanoyl-CoA or lauryl-carnitine. In conclusion, 5-HD is activated, transported into mitochondria and metabolised via β-oxidation, albeit with rate-limiting kinetics at the penultimate step. This creates a bottleneck for β-oxidation of fatty acids. The complex metabolic effects of 5-HD invalidate the use of 5-HD as a blocker of mitochondrial K ATP channels in studies of preconditioning.
Mitochondrial β-oxidation of saturated fatty acids in humans
Mitochondrion, 2018
Mitochondrial β-oxidation of fatty acids generates acetyl-coA, NADH and FADH 2. Acyl-coA synthetases catalyze the binding of fatty acids to coenzyme A to form fatty acyl-coA thioesters, the first step in the intracellular metabolism of fatty acids. L-carnitine system facilitates the transport of fatty acyl-coA esters across the mitochondrial membrane. Carnitine palmitoyltransferase-1 transfers acyl groups from coenzyme A to L-carnitine, forming acyl-carnitine esters at the outer mitochondrial membrane. Carnitine acyl-carnitine translocase exchanges acyl-carnitine esters that enter the mitochondria, by free L-carnitine. Carnitine palmitoyltransferase-2 converts acyl-carnitine esters back to acyl-coA esters at the inner mitochondrial membrane. The β-oxidation pathway of fatty acyl-coA esters includes four reactions. Fatty acyl-coA dehydrogenases catalyze the introduction of a double bond at the C2 position, producing 2-enoyl-coA esters and reducing equivalents that are transferred to the respiratory chain via electron transferring flavoprotein. Enoyl-coA hydratase catalyzes the hydration of the double bond to generate a 3-L-hydroxyacyl-coA derivative. 3-L-hydroxyacyl-coA dehydrogenase catalyzes the formation of a 3-ketoacyl-coA intermediate. Finally, 3-ketoacyl-coA thiolase catalyzes the cleavage of the chain, generating acetyl-coA and a fatty acyl-coA ester two carbons shorter. Mitochondrial trifunctional protein catalyzes the three last steps in the β-oxidation of long-chain and medium-chain fatty acyl-coA esters while individual enzymes catalyze the β-oxidation of short-chain fatty acyl-coA esters. Clinical phenotype of fatty acid oxidation disorders usually includes hypoketotic hypoglycemia triggered by fasting or infections, skeletal muscle weakness, cardiomyopathy, hepatopathy, and neurological manifestations. Accumulation of non-oxidized fatty acids promotes their conjugation with glycine and Lcarnitine and alternate ways of oxidation, such as ω-oxidation.
Chemistry & Biology, 2003
vent apoptosis [10]. Glutathione is of vital importance for maintenance of Institute of Medicine Haukeland University Hospital cellular redox homeostasis, and deprivation of glutathione typically results in severe oxidative damage associ-N-5021 Bergen 3 Department of Anatomy and Cell Biology ated with mitochondrial degeneration (reviewed in [11]). Activation of apoptosis may occasionally include in-University of Bergen Å rstadveien 19 creased generation of reactive oxygen species (ROS) [12], and is sometimes accompanied by cellular glutathi-N-5009 Bergen Norway one depletion [13-15]. In accordance, experimental modulation of cellular thiols has been reported to affect the cellular resistance to apoptosis [16, 17], supporting the theory that increased levels of glutathione may be Summary associated with drug and radiation resistance of malignant cells [11, 18].
Biochimica et Biophysica Acta (BBA) - Bioenergetics, 2010
The present state of the art in studies on the mechanisms of antioxidant activities of mitochondria-targeted cationic plastoquinone derivatives (SkQs) is reviewed. Our experiments showed that these compounds can operate as antioxidants in two quite different ways, i.e. (i) by preventing peroxidation of cardiolipin [Antonenko et al., Biochemistry (Moscow) 73 (2008) 1273-1287] and (ii) by fatty acid cycling resulting in mild uncoupling that inhibits the formation of reactive oxygen species (ROS) in mitochondrial State 4 [Severin et al. Proc. Natl. Acad. Sci. USA 107 (2009), 663-668]. The quinol and cationic moieties of SkQ are involved in cases (i) and (ii), respectively. In case (i) SkQH 2 interrupts propagation of chain reactions involved in peroxidation of unsaturated fatty acid residues in cardiolipin, the formed SkQ• − being reduced back to SkQH 2 by heme b H of complex III in an antimycin-sensitive way. Molecular dynamics simulation showed that there are two stable conformations of SkQ1 with the quinol residue localized near peroxyl radicals at C 9 or C 13 of the linoleate residue in cardiolipin. In mechanism (ii), fatty acid cycling mediated by the cationic SkQ moiety is involved. It consists of (a) transmembrane movement of the fatty acid anion/SkQ cation pair and (b) back flows of free SkQ cation and protonated fatty acid. The cycling results in a protonophorous effect that was demonstrated in planar phospholipid membranes and liposomes. In mitochondria, the cycling gives rise to mild uncoupling, thereby decreasing membrane potential and ROS generation coupled to reverse electron transport in the respiratory chain. In yeast cells, dodecyltriphenylphosphonium (С 12 TPP), the cationic part of SkQ1, induces uncoupling that is mitochondria-targeted since С 12 TPP is specifically accumulated in mitochondria and increases the H + conductance of their inner membrane. The conductance of the outer cell membrane is not affected by С 12 TPP.
The Biochemical journal, 1990
1. The effects of 3-, 4- and 5-thia-substituted fatty acids on mitochondrial and peroxisomal beta-oxidation have been investigated. When the sulphur atom is in the 4-position, the resulting thia-substituted fatty acid becomes a powerful inhibitor of beta-oxidation. 2. This inhibition cannot be explained in terms of simple competitive inhibition, a phenomenon which characterizes the inhibitory effects of 3- and 5-thia-substituted fatty acids. The inhibitory sites for 4-thia-substituted fatty acids are most likely to be the acyl-CoA dehydrogenase in mitochondria and the acyl-CoA oxidase in peroxisomes. 3. The inhibitory effect of 4-thia-substituted fatty acids is expressed both in vitro and in vivo. The effect in vitro is instantaneous, with up to 95% inhibition of palmitoylcarnitine oxidation. The effect in vivo, in contrast, is dose-dependent and increases with duration of treatment. 4. Pretreatment of rats with a 3-thia-substituted fatty acid rendered mitochondrial beta-oxidation l...