Identification of 4-aminopyrazolopyrimidine metabolite that may contribute to the hypolipidemic effects of LY2584702 in long evans diet-induced obese rats

Journal of Pharmacology and Experimental Therapeutics

Volumn 362, Issue 1, 2017, Pages 108-118

  Estridge, Thomas B ^a   Dey, Asim B ^a   Reidy, Charles ^a   Yu, Xiaohong ^a   Zhang, Yuke ^a   Hartley, Maryalice ^a   Milligan, Paul L ^a   Jin, Najia ^a   Kowala, Mark C ^a   Leohr, Jennifer K ^a   Fretland, Adrian J ^a   Mabry, Thomas E ^a   Luffer Atlas, Debra ^a   Luo, M Jane ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 AMINOPYRAZOLO[3,4 DAY]PYRIMIDINE; 4 AMINOPYRAZOLO[3,4 D]PYRIMIDINE; LOMITAPIBE; LOW DENSITY LIPOPROTEIN CHOLESTEROL; MESSENGER RNA; MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN INHIBITOR; S6 KINASE; TRIACYLGLYCEROL; UNCLASSIFIED DRUG; VERY LOW DENSITY LIPOPROTEIN CHOLESTEROL; 4-AMINOPYRAZOLO(3,4-D)PYRIMIDINE; ADENINE; ANTILIPEMIC AGENT; LOW DENSITY LIPOPROTEIN; LY2584702; PYRAZOLE DERIVATIVE; PYRIMIDINE DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CHOLESTEROL BLOOD LEVEL; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG ELIMINATION; DRUG EXCRETION; DRUG METABOLISM; DRUG RESPONSE; DRUG STRUCTURE; DRUG TOLERABILITY; DYSLIPIDEMIA; GENE EXPRESSION; HEP-G2 CELL LINE; HUMAN; HUMAN CELL; LIPID METABOLISM; LONG EVANS RAT; NONHUMAN; OBESITY; PRIORITY JOURNAL; PROTEIN METABOLISM; RAT; TREATMENT DURATION; TREATMENT OUTCOME; TRIACYLGLYCEROL BLOOD LEVEL; ANALOGS AND DERIVATIVES; ANIMAL; BIOSYNTHESIS; BLOOD; DRUG EFFECTS; GENE EXPRESSION REGULATION; GENETICS; LIVER; MALE; METABOLISM;

ADENINE; ANIMALS; CHOLESTEROL, LDL; CHOLESTEROL, VLDL; GENE EXPRESSION REGULATION; HEP G2 CELLS; HUMANS; HYPOLIPIDEMIC AGENTS; LIPID METABOLISM; LIPOPROTEINS, LDL; LIVER; MALE; OBESITY; PYRAZOLES; PYRIMIDINES; RATS; RATS, LONG-EVANS; TRIGLYCERIDES;

EID: 85020993483     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.117.240242     Document Type: Article

References (28)

1. Arendt BM, Ma DW, Simons B, Noureldin SA, Therapondos G, Guindi M, Sherman M, Allard JP (2013) Nonalcoholic fatty liver disease is associated with lower hepatic and erythrocyte ratios of phosphatidylcholine to phosphatidylethanolamine. Appl Physiol Nutr Metab 38: 334-340
2. Cameron J, Ranheim T, Kulseth MA, Leren TP, and Berge KE (2008) Berberine decreases PCSK9 expression in HepG2 cells. Atherosclerosis 201:266-273.
3. Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG, Bernier L, and Prat A (2004) Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 24:1454-1459.
4. Funatsu T, Kakuta H, Takasu T, and Miyata K (2002) Atorvastatin increases hepatic fatty acid beta-oxidation in sucrose-fed rats: comparison with an MTP inhibitor. Eur J Pharmacol 455:161-167.
5. Goldstein JL and Brown MS (2015) A century of cholesterol and coronaries: from plaques to genes to statins. Cell 161:161-172.
6. Han B, Eacho PI, Knierman MD, Troutt JS, Konrad RJ, Yu X, and Schroeder KM (2014) Isolation and characterization of the circulating truncated form of PCSK9. J Lipid Res 55:1505-1514.
7. Henderson JF (1963) Studies on Fatty Liver Induction by 4-Aminopyrazolopyrimidine. J Lipid Res 4:68-74.
8. Henderson JF and Junga IG (1961) The metabolism of 4-aminopyrazolo(3,4-d)pyrimidine in normal and neoplastic tissues. Cancer Res 21:118-129.
9. Hollebecque A, Houédé N, Cohen EE, Massard C, Italiano A, Westwood P, Bumgardner W, Miller J, Brail LH, Benhadji KA, et al. (2014) A phase Ib trial of LY2584702 tosylate, a p70 S6 inhibitor, in combination with erlotinib or everolimus in patients with solid tumours. Eur J Cancer 50:876-884.
10. Horton JD, Cohen JC, and Hobbs HH (2009) PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res 50 (Suppl):S172-S177.
11. Horton JD, Shah NA, Warrington JA, Anderson NN, Park SW, Brown MS, and Goldstein JL (2003) Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci USA 100:12027-12032.
12. Kieft KA, Bocan TM, and Krause BR (1991) Rapid on-line determination of cholesterol distribution among plasma lipoproteins after high-performance gel filtration chromatography. J Lipid Res 32:859-866.
13. Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, Wang Y, Wang Z, Si S, Pan H, et al. (2004) Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med 10:1344-1351.
14. Krause BR, Sloop CH, and Roheim PS (1981) Lipid absorption in unanesthetized, unrestrained rats. Effects of 4-aminopyrazolopyrimidine and ethinyl estradiol. Biochim Biophys Acta 665:165-169.
15. Li S, Ogawa W, Emi A, Hayashi K, Senga Y, Nomura K, Hara K, Yu D, and KasugaM (2011) Role of S6K1 in regulation of SREBP1c expression in the liver. Biochem Biophys Res Commun 412:197-202.
16. Li S, Zhang HY, Hu CC, Lawrence F, Gallagher KE, Surapaneni A, Estrem ST, Calley JN, Varga G, Dow ER, et al. (2008) Assessment of diet-induced obese rats as an obesity model by comparative functional genomics. Obesity (Silver Spring) 16: 811-818.
17. Magnuson B, Ekim B, and Fingar DC (2012) Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks. Biochem J 441:1-21.
18. Newsom SA, Brozinick JT, Kiseljak-Vassiliades K, Strauss AN, Bacon SD, Kerege AA, Bui HH, Sanders P, Siddall P, Wei T, et al. (2016) Skeletal muscle phosphatidylcholine and phosphatidylethanolamine are related to insulin sensitivity and respond to acute exercise in humans. J Appl Physiol 120: 1355-1363
19. Owen JL, Zhang Y, Bae SH, Farooqi MS, Liang G, Hammer RE, Goldstein JL, and Brown MS (2012) Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase. Proc Natl Acad Sci USA 109: 16184-16189.
20. Pearce LR, Komander D, and Alessi DR (2010) The nuts and bolts of AGC protein kinases. Nat Rev Mol Cell Biol 11:9-22.
21. Rader DJ and Kastelein JJ (2014) Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation 129:1022-1032.
22. Ricoult SJ and Manning BD (2013) The multifaceted role of mTORC1 in the control of lipid metabolism. EMBO Rep 14:242-251.
23. Seidah NG, Awan Z, Chrétien M, and Mbikay M (2014) PCSK9: a key modulator of cardiovascular health. Circ Res 114:1022-1036.
24. Shaw RK, Shulman RN, Davidson JD, Rall DP, and Frei, 3rdE (1960) Studies with the experimental antitumor agent 4-aminopyrazolo[3, 4-d]pyrimidine. Cancer 13: 482-489.
25. Shiff TS, Roheim PS, and Eder HA (1971) Effects of high sucrose diets and 4-aminopyrazolopyrimidine on serum lipids and lipoproteins in the rat. J Lipid Res 12:596-603.
26. Tolcher A, Goldman J, Patnaik A, Papadopoulos KP, Westwood P, Kelly CS, Bumgardner W, Sams L, Geeganage S,Wang T, et al. (2014) A phase I trial of LY2584702 tosylate, a p70 S6 kinase inhibitor, in patients with advanced solid tumours. Eur J Cancer 50: 867-875.
27. Wang Y, Viscarra J, Kim SJ, and Sul HS (2015) Transcriptional regulation of hepatic lipogenesis. Nat Rev Mol Cell Biol 16:678-689.
28. Wilkening S, Stahl F, and Bader A (2003) Comparison of primary human hepatocytes and hepatoma cell line Hepg2 with regard to their biotransformation properties. Drug Metab Dispos 31:1035-1042.