DGAT1 inhibitors as anti-obesity and anti-diabetic agents

Current Opinion in Drug Discovery and Development

Volumn 13, Issue 4, 2010, Pages 489-496

  Birch, Alan M ^a   Buckett, Linda K ^a   Turnbull, Andrew V ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

DGAT1 inhibitor; diabetes; diacylglycerol acyl transferase 1; medicinal chemistry; metabolic syndrome; obesity; therapeutic

Indexed keywords

A 922500; ANTIDIABETIC AGENT; ANTIOBESITY AGENT; BAY 74 4113; BAY 744113; CARBOXYLIC ACID DERIVATIVE; DIACYLGLYCEROL ACYLTRANSFERASE 1; ENZYME INHIBITOR; FATTY ACID; GLUCAGON LIKE PEPTIDE 1; INSULIN; JNJ 40569321; PF 04620110; RETINOID; SESQUITERPENOID; TRIACYLGLYCEROL; UNCLASSIFIED DRUG; DGAT1 PROTEIN, HUMAN; DIACYLGLYCEROL ACYLTRANSFERASE;

ALOPECIA; APOPTOSIS; ATHEROSCLEROSIS; BODY WEIGHT; DIABETES MELLITUS; DRUG BIOAVAILABILITY; DRUG PENETRATION; DRUG SOLUBILITY; DYSLIPIDEMIA; ENERGY EXPENDITURE; ENZYME ACTIVITY; ENZYME INHIBITION; FATTY ACID OXIDATION; FATTY LIVER; GENE DELETION; GENE OVEREXPRESSION; GLUCOSE HOMEOSTASIS; HUMAN; INFLAMMATION; INSULIN BLOOD LEVEL; INSULIN RESISTANCE; INSULIN SENSITIVITY; LIPID DIET; METABOLIC CLEARANCE RATE; METABOLIC DISORDER; MUSCLE FUNCTION; NONHUMAN; OBESITY; PHENOTYPE; PLASMA PROTEIN BINDING; REVIEW; SKIN FUNCTION; TRANSGENIC MOUSE; ANIMAL; ANTAGONISTS AND INHIBITORS; METABOLISM;

ANIMALS; DIABETES MELLITUS; DIACYLGLYCEROL O-ACYLTRANSFERASE; HUMANS; HYPOGLYCEMIC AGENTS; OBESITY;

EID: 77954647349     PISSN: 13676733     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (46)

1. Zammit VA, Buckett LK, Turnbull AV, Wure H, Proven A: Diacylglycerol acyltransferases: Potential roles as pharmacological targets. Pharmacol Ther (2008)118(3):295-302.
2. Hubbard BK, Enyedy I, Gilmore TA, Serrano-Wu MH: Antisense and small-molecule modulation of diacylglycerol acyltransferase. Expert Opin Ther Pat (2007)17(11):1331-1339.
3. Matsuda D, Tomoda H: DGAT inhibitors for obesity. Curr Opin Invest Drugs (2007)8(10):836-841.
4. Chen HC, Farese RV Jr: Inhibition of triglyceride synthesis as a treatment strategy for obesity: Lessons from DGAT1-deficient mice. Arterioscler Thromb Vasc Biol (2005) 25: 482-486.
5. Buhman KK, Smith SJ, Stone SJ, Repa JJ, Wong JS, Knapp FF Jr, Burri BJ, Hamilton RL, Abumrad NA, Farese RV Jr: DGAT1 is not essential for intestinal triacylglycerol absorption or chylomicron synthesis. J Biol Chem (2002)277(28):25474-25479.
6. Okawa M, Fujii K, Ohbuchi K, Okumoto M, Aragane K, Sato H, Tamai Y, Seo T, Itoh Y, Yoshimoto R: Role of MGAT2 and DGAT1 in the release of gut peptides after triglyceride ingestion. Biochem Biophys Res Commun (2009)390(3):377-381. •• DGAT1 deficiency prolonged the release of GLP-1 and PYY after a loaded fat diet, and delayed gastric emptying.
7. -/- mice. J Lipid Res (2010)51(7):1770-1780. •• DGAT1 stimulated fat secretion from enterocytes and thus determined the metabolic consequences of deposition of the fat in other tissues.
8. Chen HC, Jensen DR, Myers HM, Eckel RH, Farese RV Jr: Obesity resistance and enhanced glucose metabolism in mice transplanted with white adipose tissue lacking acyl CoA:diacylglycerol acyltransferase 1. J Clin Invest (2003)111(11):1715-1722.
9. Chen HC, Ladha Z, Smith SJ, Farese RV Jr: Analysis of energy expenditure at different ambient temperatures in mice lacking DGAT1. Am J Physiol (2003)284(1):E213-E218.
10. Smith SJ, Cases S, Jensen DR, Chen HC, Sande E, Tow B, Sanan DA, Raber J, Eckel RH, Farese RV Jr: Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking DGAT. Nat Genet (2000)25(1):87-90.
11. Birtles S, Buckett L, Hammon C, Turnbull A: Pharmacological effect of DGAT1 inhibition on food intake and post-prandial lipaemia - Determination of the mechanism of action. Proc Physiol Soc (2010) 18: Abs PC28
12. Villanueva CJ, Monetti M, Shih M, Zhou P, Watkins SM, Bhanot S, Farese RV Jr: Specific role for acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) in hepatic steatosis due to exogenous fatty acids. Hepatology (2009)50(2):434-442. • Describes the role of DGAT1 in hepatic steatosis induced by the delivery of exogenous, but not de novo synthesized, fatty acids to the liver. DGAT1 deficiency was protective against steatosis by reducing fatty acid synthesis and increasing oxidation.
13. Fabbrini E, Sullivan S, Klein S: Obesity and nonalcoholic fatty liver disease: Biochemical, metabolic, and clinical implications. Hepatology (2010)51(2):679-689.
14. Yamaguchi K, Yang L, McCall S, Huang J, Yu XX, Pandey SK, Bhanot S, Monia BP, Li Y, Diehl AM: Diacylglycerol acyltranferase 1 anti-sense oligonucleotides reduce hepatic fibrosis in mice with nonalcoholic steatohepatitis. Hepatology (2008)47(2):625-635.
15. Choi CS, Savage DB, Kulkarni A, Yu XX, Liu ZX, Morino K, Kim S, Distefano A, Samuel VT, Neschen S, Zhang D et al: Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. J Biol Chem (2007)282(31):22678-22688.
16. Liu L, Shi X, Bharadwaj KG, Ikeda S, Yamashita H, Yagyu H, Schaffer JE, Yu YH, Goldberg IJ: DGAT1 expression increases heart triglyceride content but ameliorates lipotoxicity. J Biol Chem (2009)284(52):36312-36323.
17. Liu L, Shi X, Choi CS, Shulman GI, Klaus K, Nair KS, Schwartz GJ, Zhang Y, Goldberg IJ, Yu YH: Paradoxical coupling of triglyceride synthesis and fatty acid oxidation in skeletal muscle overexpressing DGAT1. Diabetes (2009)58(11):2516-2524.
18. Koliwad SK, Streeper RS, Monetti M, Cornelissen I, Chan L, Terayama K, Naylor S, Rao M, Hubbard B, Farese RV Jr: DGAT1-dependent triacylglycerol storage by macrophages protects mice from diet-induced insulin resistance and inflammation. J Clin Invest (2010)120(3):756-767.
19. Shih MY, Kane MA, Zhou P, Yen CL, Streeper RS, Napoli JL, Farese RV Jr: Retinol esterification by DGAT1 is essential for retinoid homeostasis in murine skin. J Biol Chem (2009)284(7):4292-4299.
20. Cases S, Stone SJ, Zhou P, Yen E, Tow B, Lardizabal KD, Voelker T, Farese RV Jr: Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members. J Biol Chem (2001)276(42):38870-38876.
21. Stone SJ, Myers HM, Watkins SM, Brown BE, Feingold KR, Elias PM, Farese RV Jr: Lipopenia and skin barrier abnormalities in DGAT2-deficient mice. J Biol Chem (2004)279(12):11767-11776.
22. Yu XX, Murray SF, Pandey SK, Booten SL, Bao D, Song XZ, Kelly S, Chen S, McKay R, Monia BP, Bhanot S: Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice. Hepatology (2005)42(2):362-371.
23. Zhao G, Souers AJ, Voorbach M, Falls HD, Droz B, Brodjian S, Lau YY, Iyengar RR, Gao J, Judd AS, Wagaw SH et al: Validation of diacyl glycerolacyltransferase I as a novel target for the treatment of obesity and dyslipidemia using a potent and selective small molecule inhibitor. J Med Chem (2008)51(3):380-383. •• First account of the discovery and pharmacological profile of a series of small-molecule DGAT1 inhibitors, providing validation of the target for the potential treatment of obesity and dyslipidemia.
24. Birch AM, Birtles S, Buckett LK, Kemmitt PD, Smith GJ, Smith TJ, Turnbull AV, Wang SJ: Discovery of a potent, selective, and orally efficacious pyrimidinooxazinyl bicyclooctaneacetic acid diacylglycerol acyltransferase-1 inhibitor. J Med Chem (2009)52(6):1558-1568. • Second account of the development and properties of small-molecule DGAT1 inhibitors, including the first description of the effects of DGAT1 inhibitors in adipose tissue.
25. Dow R: Discovery of PF-04620110: A selective DGAT1 inhibitor for the treatment of type 2 diabetes. Metabolic Diseases Drug Discovery & Development, Half Moon Bay, CA, USA (2009).
26. Yun W, Bolin DR, Li S, Ahmad M, Wertheimer SJ, Conde-Knape K, Chen Y, Kazmer S: Discovery and optimization of oxazole based diacylglycerol acyltransferase 1 inhibitors for the treatment of obesity. 237th ACS National Meeting, Salt Lake City, UT, USA (2009): Abs MEDI-256.
27. Linders JTM, Roevens P, Berwaer M, Boeckx S, Bongartz J-P, Borghys H, Buyck C, Coesemans E, Davidenko PV, Gilissen RAHJ, Govaerts T et al: Discovery, synthesis, and in vivo activity of phenylpiperazine DGAT1 inhibitors for the treatment of metabolic syndrome. 238th ACS National Meeting, Washington DC, USA (2009): Abs MEDI-372.
28. Park HR, Yoo MY, Seo JH, Kim IS, Kim NY, Kang JY, Cui L, Lee CS, Lee CH, Lee HS: Sesquiterpenoids isolated from the flower buds of Tussilago farfara L inhibit diacylglycerol acyltransferase. J Agric Food Chem (2008)56(22):10493- 10497.
29. Oh WK, Lee C, Seo JH, Chung MY, Cui L, Fomum ZT, Kang JS, Lee HS: Diacylglycerol acyltransferase-inhibitory compounds from Erythrina senegalensis. Arch Pharm Res (2009)32(1):43-47.
30. Song M, Yang H, Cho J, Chung I, Kwon B, Kim D, Baek N: Glycerides from the aerial parts of garland (Chrysanthemum coronarium L.) and their inhibitory effects on ACAT, DGAT, FPTase, and β-secretase. Food Sci Biotechnol (2009)18(1):95-102.
31. Lee SW, Rho M, Choi J, Kim K, Choi YS, Lee HS, Kim YK: Inhibition of diacylglycerol acyltransferase by phenylpyropenes produced by Penicillim griseofulvum F1959. J Microbiol Biotechnol (2008)18(11):1785-1788.
32. King AJ, Judd AS, Souers AJ: Inhibitors of diacylglycerol acyltransferase: A review of 2008 patents. Expert Opin Ther Pat (2010)20(1):19-29.
33. Nissan Chemical Industries Ltd/Taisho Pharmaceutical Co Ltd (Umemiya H, Takahashi M Heteroarylbenzene compounds. WO-2009011285 (2009).
34. Bristol-Myers Squibb Co (Huang Y, Sun C, Lawrence MR, Ewing WR, Turdi H) Triazolo compounds useful as DGAT1 inhibitors. WO-2009126624 (2009).
35. Novartis AG (Forster CJ, Kwak Y-S, Nakajima K, Wang B Organic compounds. WO-2010007046 (2010).
36. Wertheimer SJ, Conde-Knape K, Qian Y, Bolin DR, Yun W, Firooznia F, Cheung A, McDermott L, Ramsey GB, Kazmer S, Chen Y et al: Can DGAT inhibition improve insulin sensitivity? 69th Annual Meeting of the American Diabetes Association, New Orleans, LA, USA (2009): 1279.
37. Chen HC, Smith SJ, Ladha Z, Jensen DR, Ferreira LD, Pulawa LK, McGuire JG, Pitas RE, Eckel RH, Farese RV Jr. Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1. J Clin Invest (2002)109(8):1049-1055.
38. King AJ, Segreti JA, Larson KJ, Souers AJ, Kym PR, Reilly RM, Zhao G, Mittelstadt SW, Cox BF: Diacylglycerol acyltransferase 1 inhibition lowers serum triglycerides in the Zucker fatty rat and the hyperlipidemic hamster. J Pharmacol Exp Ther (2009)330(2):526-531. •• DGAT1 inhibitors reduced plasma TAG levels in rodent models of dyslipidemia, and also had more wide-ranging beneficial effects on dyslipidemic parameters beyond TAG lowering
39. Amgen Inc/Japan Tobacco Inc (Ogawa N, Okuma C, Furukawa N Anorectic compounds. WO-2005072740 (2005).
40. Novartis AG (Bose A, Thompson J Method of increasing cellular phosphatidyl choline by DGAT1 inhibition. WO-2009112445 (2009).
41. Novartis AG (Bose A, Hughes TE Method of treatment. WO-2008073865 (2008).
42. Pfizer Inc: Pfizer enters into agreement with Bayer to license compounds for potential treatment of obesity, diabetes and related disorders. Press Release (2006): June 14.
43. AstraZeneca pipeline summary: AstraZeneca plc, London, UK (2010). www.astrazeneca.com/research/our-pipeline-summary
44. King AJ, Segreti JA, Larson KJ, Souers AJ, Kym PR, Reilly RM, Collins CA, Voorbach MJ, Zhao G, Mittelstadt SW, Cox BF: In vivo efficacy of acyl CoA: Diacylglycerol acyltransferase (DGAT) 1 inhibition in rodent models of postprandial hyperlipidaemia. Eur J Pharmacol (2010)637(1-3):155-161.
45. Wang SJ, Cornick C, O'Dowd J, Cawthorne MA, Arch JR: Improved glucose tolerance in acyl CoA:diacylglycerol acyltransferase 1-null mice is dependent on diet. Lipids Health Dis (2007) 6: 2
46. Chen HC, Smith SJ, Tow B, Elias PM, Farese RV Jr: Leptin modulates the effects of acyl CoA:diacylglycerol acyltransferase defciency on murine fur and sebaceous glands. J Clin Invest (2002)109(2):175-181.