Pirinixic acid

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Pirinixic acid
Pirinixic acid.svg
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
ECHA InfoCard 100.150.489
Chemical and physical data
Formula C14H14ClN3O2S
Molar mass 323.8 g/mol
3D model (Jmol)

Pirinixic acid is a peroxisome proliferator-activated receptor alpha (PPARα) agonist that is under experimental investigation for prevention of severe cardiac dysfunction, cardiomyopathy and heart failure as a result of lipid accumulation within cardiac myocytes.[1] Treatment is primarily aimed at individuals with an adipose triglyceride lipase (ATGL) enzyme deficiency or mutation[2] because of the essential PPAR protein interactions with free fatty acid monomers derived from the ATGL catalyzed lipid oxidation reaction.[3] It was discovered as WY-14,643 in 1974.[4]

Adipose triglyceride lipase (ATGL)[edit]

Adipose triglyceride lipase (ATGL), an enzyme that catalyzes the rate limiting hydrolysis step of triglycerides[5] in the triacylglycerol lipolysis cascade, is expressed predominantly in adipose tissue, but is also found in lesser amounts within cardiac and skeletal muscle.[6] Its function is to initiate the breakdown of intracellular triglycerides into fatty acid monomers.[7] Individuals deficient in the ATGL enzyme are at higher risk for cardiac dysfunction and premature death because of increased size and accumulation of lipid droplets within cardiac myocytes.[8]

Peroxisome proliferator activated receptors (PPARs)[edit]

PPARs are a family of ligand activated receptors which include PPARα, PPARδ and PPARγ subtypes that are expressed in varying amounts in nuclear membranes of in different tissues.[9] PPAR activation occurs with free fatty acid binding, or fatty acid derivative ligands that have been broken down via the triacylglycerol lipolysis cascade.[10] Activated PPARs act as transcription factors to increase expression of specific genes within cells.[11] PPARα, a PPAR subtype, controls the expression of genes involved in cardiac fatty acid utilization,[12][13] and its activation, stimulates free fatty acid oxidation by increasing mitochondrial free fatty acid uptake and oxidation via two enzymes: carnitine palmitoyltransferase I (M-CPT I) and medium-chain acyl-CoA dehydrogenase (MCAD).[14]

Pre-clinical trials[edit]

ATGL deficient mice administered pirinixic acid demonstrated reduced cardiac hypertrophy and improved cardiac function.[15] These data demonstrate that genes induced by PPARα activation via free fatty acids from ATGL-dependent reactions are essential for the maintenance of normal cardiac function.[16] As PPARα activation triggers the expression of genes involved in lipid metabolism (M-CPTI I and MCAD),[17] treating the mice with pirinixic acid may improve cardiac myocyte energy supply by increasing mitochondrial fatty acid β-oxidation to prevent severe cardiac dysfunction as a result of lipid accumulation .

References[edit]

  1. ^ Wölkart, G.; Schrammel, A.; Dörffe, K.; Kaemmerle, G.; Zechner, R.; Mayer, B. (2012). "Cardiac dysfunction in adipose triglyceride lipase deficiency: treatment with a PPARα agonist". British Journal of Pharmacology. 165 (2): 380–389. doi:10.1111/j.1476-5381.2011.01490.x. 
  2. ^ Wölkart, G.; Schrammel, A.; Dörffe, K.; Kaemmerle, G.; Zechner, R.; Mayer, B. (2012). "Cardiac dysfunction in adipose triglyceride lipase deficiency: treatment with a PPARα agonist". British Journal of Pharmacology. 165 (2): 380–389. doi:10.1111/j.1476-5381.2011.01490.x. 
  3. ^ Wölkart, G.; Schrammel, A.; Dörffe, K.; Kaemmerle, G.; Zechner, R.; Mayer, B. (2012). "Cardiac dysfunction in adipose triglyceride lipase deficiency: treatment with a PPARα agonist". British Journal of Pharmacology. 165 (2): 380–389. doi:10.1111/j.1476-5381.2011.01490.x. 
  4. ^ Santilli, A. A.; Scotese, A. C.; Tomarelli, R. M. (1974). "A potent antihypercholesterolemic agent: [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14643)". Experientia. 30 (10): 1110–1. PMID 4435102. doi:10.1007/BF01923636. 
  5. ^ Zimmermann, R.; Strauss, J.G.; Haemmerle, G.; Schoiswohl, G.; Birner-Gruenberger, R.; Riederer, M. (2004). "Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase.". Science. 306: 1383–1386. PMID 15550674. doi:10.1126/science.1100747. 
  6. ^ Zimmermann, R.; Strauss, J.G.; Haemmerle, G.; Schoiswohl, G.; Birner-Gruenberger, R.; Riederer, M. (2004). "Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase.". Science. 306: 1383–1386. PMID 15550674. doi:10.1126/science.1100747. 
  7. ^ Wölkart, G.; Schrammel, A.; Dörffe, K.; Kaemmerle, G.; Zechner, R.; Mayer, B. (2012). "Cardiac dysfunction in adipose triglyceride lipase deficiency: treatment with a PPARα agonist". British Journal of Pharmacology. 165 (2): 380–389. doi:10.1111/j.1476-5381.2011.01490.x. 
  8. ^ Haemmerle, G.; Lass, A.; Zimmermann, R.; Gorkiewicz, G.; Meyer, C.; Rozman, J. (2006). "Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase.". Science. 312: 734–737. PMID 16675698. doi:10.1126/science.1123965. 
  9. ^ Braissant, O.; Foufelle, F.; Scotto, C.; Dauca, M.; Wahli, W. (1996). "Differential expression of peroxisome proliferator-activated receptors (PPARs):tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat.". Endocrinology. 137 (1): 354–366. PMID 8536636. doi:10.1210/endo.137.1.8536636. 
  10. ^ Wölkart, G.; Schrammel, A.; Dörffe, K.; Kaemmerle, G.; Zechner, R.; Mayer, B. (2012). "Cardiac dysfunction in adipose triglyceride lipase deficiency: treatment with a PPARα agonist". British Journal of Pharmacology. 165 (2): 380–389. doi:10.1111/j.1476-5381.2011.01490.x. 
  11. ^ Djouadi, F.; Brandt, J.; Weinheimer, J.; Leone, T.C.; Gonzalez, J.; Kelly, D.P. (1999). "The role of peroxisome proliferator-activated receptor α (PPARα)in the control of cardiac lipid metabolism". Prostaglandins, Leukotrienes and Essential Fatty Acids. 60: 339–343. doi:10.1016/s0952-3278(99)80009-x. 
  12. ^ Djouadi, F.; Brandt, J.; Weinheimer, J.; Leone, T.C.; Gonzalez, J.; Kelly, D.P. (1999). "The role of peroxisome proliferator-activated receptor α (PPARα)in the control of cardiac lipid metabolism". Prostaglandins, Leukotrienes and Essential Fatty Acids. 60: 339–343. doi:10.1016/s0952-3278(99)80009-x. 
  13. ^ Fruchard, J.; Duriez, P.; Steals, B. (1999). "Peroxisome Proliferator-Activated Receptor Alpha activators regulate genes governming lipoprotein metabolism, vascular inflammation and atherosclerosis". Current Opinion in Lipidology. 10 (3): 245–257. doi:10.1097/00041433-199906000-00007. 
  14. ^ Djouadi, F.; Brandt, J.; Weinheimer, J.; Leone, T.C.; Gonzalez, J.; Kelly, D.P. (1999). "The role of peroxisome proliferator-activated receptor α (PPARα)in the control of cardiac lipid metabolism". Prostaglandins, Leukotrienes and Essential Fatty Acids. 60: 339–343. doi:10.1016/s0952-3278(99)80009-x. 
  15. ^ Wölkart, G.; Schrammel, A.; Dörffe, K.; Kaemmerle, G.; Zechner, R.; Mayer, B. (2012). "Cardiac dysfunction in adipose triglyceride lipase deficiency: treatment with a PPARα agonist". British Journal of Pharmacology. 165 (2): 380–389. doi:10.1111/j.1476-5381.2011.01490.x. 
  16. ^ Wölkart, G.; Schrammel, A.; Dörffe, K.; Kaemmerle, G.; Zechner, R.; Mayer, B. (2012). "Cardiac dysfunction in adipose triglyceride lipase deficiency: treatment with a PPARα agonist". British Journal of Pharmacology. 165 (2): 380–389. doi:10.1111/j.1476-5381.2011.01490.x. 
  17. ^ Djouadi, F.; Brandt, J.; Weinheimer, J.; Leone, T.C.; Gonzalez, J.; Kelly, D.P. (1999). "The role of peroxisome proliferator-activated receptor α (PPARα)in the control of cardiac lipid metabolism". Prostaglandins, Leukotrienes and Essential Fatty Acids. 60: 339–343. doi:10.1016/s0952-3278(99)80009-x.