Pirinixic acid

Pirinixic acid

Identifiers
IUPAC name 2-({4-chloro-6-[(2,3-dimethylphenyl)amino]pyrimidin-2-yl}sulfanyl)acetic acid
CAS Number	50892-23-4
PubChem (CID)	5694
IUPHAR/BPS	2666
ChemSpider	5492
UNII	86C4MRT55A
ChEMBL	CHEMBL295416
ECHA InfoCard	100.150.489
Chemical and physical data
Formula	C14H14ClN3O2S
Molar mass	323.8 g/mol
3D model (Jmol)	Interactive image
SMILES Cc1cccc(c1C)Nc2cc(nc(n2)SCC(=O)O)Cl
InChI InChI=1S/C14H14ClN3O2S/c1-8-4-3-5-10(9(8)2)16-12-6-11(15)17-14(18-12)21-7-13(19)20/h3-6H,7H2,1-2H3,(H,19,20)(H,16,17,18) Key:SZRPDCCEHVWOJX-UHFFFAOYSA-N

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)

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)

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

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

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. doi:10.1007/BF01923636. PMID 4435102.
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. doi:10.1126/science.1100747. PMID 15550674.
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. doi:10.1126/science.1100747. PMID 15550674.
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. 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. doi:10.1210/endo.137.1.8536636. PMID 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.