2,300
Views
8
CrossRef citations to date
0
Altmetric
Short Communication

Synthesis and biological evaluation of novel thienopyrimidine derivatives as diacylglycerol acyltransferase 1 (DGAT-1) inhibitors

, , , , , & show all
Pages 227-234 | Received 25 Sep 2019, Accepted 10 Nov 2019, Published online: 22 Nov 2019

References

  • Kusminski CM, Bickel PE, Scherer PE. Targeting adipose tissue in the treatment of obesity-associated diabetes. Nat Rev Drug Discov 2016;15:639–60.
  • Subauste A, Burant CF. Dgat: novel therapeutic target for obesity and type 2 diabetes mellitus. Curr Drug Targets Immune Endocr Metabol Disord 2003;3:263–70.
  • Capeau J. Insulin resistance and steatosis in humans. Diabetes Metab 2008;34:649–57.
  • Kennedy EP. Metabolism of lipides. Annu Rev Biochem 1957;26:119–48.
  • Yen CL, Stone SJ, Koliwad S, et al. Thematic review series: glycerolipids. Dgat enzymes and triacylglycerol biosynthesis. J Lipid Res 2008;49:2283–301.
  • Bhatt-Wessel B, Jordan TW, Miller JH, Peng L. Role of dgat enzymes in triacylglycerol metabolism. Arch Biochem Biophys 2018;655:1–11.
  • Smith SJ, Cases S, Jensen DR, et al. Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking dgat. Nat Genet 2000;25:87–90.
  • Stone SJ, Myers HM, Watkins SM, et al. Lipopenia and skin barrier abnormalities in dgat2-deficient mice. J Biol Chem 2004;279:11767–76.
  • Birch AM, Buckett LK, Turnbull AV. Dgat1 inhibitors as anti-obesity and anti-diabetic agents. Curr Opin Drug Discov Devel 2010;13:489–96.
  • King AJ, Judd AS, Souers AJ. Inhibitors of diacylglycerol acyltransferase: a review of 2008 patents. Expert Opin Ther Pat 2010;20:19–29.
  • Motiwala H, Kandre S, Birar V, et al. Exploration of pyridine containing heteroaryl analogs of biaryl ureas as dgat1 inhibitors. Bioorg Med Chem Lett 2011;21:5812–7.
  • McCoull W, Addie MS, Birch AM, et al. Identification, optimisation and in vivo evaluation of oxadiazole dgat-1 inhibitors for the treatment of obesity and diabetes. Bioorg Med Chem Lett 2012;22:3873–8.
  • Meyers C, Gaudet D, Tremblay K, et al. The dgat1 inhibitor lcq908 decreases triglyceride levels in patients with the familial chylomicronemia syndrome. J Clin Lipidol 2012;6:266–7.
  • King AJ, Segreti JA, Larson KJ, et al. Diacylglycerol acyltransferase 1 inhibition lowers serum triglycerides in the zucker fatty rat and the hyperlipidemic hamster. J Pharmacol Exp Ther 2009;330:526–31.
  • Zhao G, Souers AJ, Voorbach M, 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;51:380–3.
  • Qian Y, Wertheimer SJ, Ahmad M, et al. Discovery of orally active carboxylic acid derivatives of 2-phenyl-5-trifluoromethyloxazole-4-carboxamide as potent diacylglycerol acyltransferase-1 inhibitors for the potential treatment of obesity and diabetes. J Med Chem 2011;54:2433–46.
  • Harrison TJ, Bauer D, Berdichevsky A, et al. Successful strategies for mitigation of a preclinical signal for phototoxicity in a dgat1 inhibitor. ACS Med Chem Lett 2019;10:1128–33.
  • Yu Y, Wu Z, Shi Z-C, et al. Accelerating the discovery of dgat1 inhibitors through the application of parallel medicinal chemistry (pmc). Bioorg Med Chem Lett 2019;29:1380–5.
  • Nakajima K, Chatelain R, Clairmont KB, et al. Discovery of an orally bioavailable benzimidazole diacylglycerol acyltransferase 1 (dgat1) inhibitor that suppresses body weight gain in diet-induced obese dogs and postprandial triglycerides in humans. J Med Chem 2017;60:4657–64.
  • Devani MB, Shishoo CJ, Pathak US, et al. Synthesis of 3-substituted thieno [2, 3-d] pyrimidin-4(3h)-one-2-mercaptoacetic acids and their ethyl esters for pharmacological screening. J Pharm Sci 1976;65:660–4.
  • Dow RL, Munchhof MJ, Preparation of substituted dihydropyrimidooxazepine derivatives for use as antiobesity agents. In: Preparation of substituted dihydropyrimidooxazepine derivatives for use as antiobesity agents; 20080722; WO: Pfizer Products Inc.; 2009.
  • Birch AM, Birtles S, Buckett LK, et al. Discovery of a potent, selective, and orally efficacious pyrimidinooxazinyl bicyclooctaneacetic acid diacylglycerol acyltransferase-1 inhibitor. J Med Chem 2009;52:1558–68.
  • Pramfalk C, Eriksson M, Parini P. Cholesteryl esters and acat. Eur J Lipid Sci Technol 2012;114:624–33.