Discovery and Pharmacology of a Novel Class of Diacylglycerol Acyltransferase 2 Inhibitors

Journal of Medicinal Chemistry

Volumn 58, Issue 23, 2015, Pages 9345-9353

  Imbriglio, Jason E ^a   Shen, Dong Ming ^a   Liang, Rui ^a   Marby, Ken ^a   You, Ming ^a   Youm, Hye Won ^a   Feng, Zhe ^a   London, Clare ^a   Xiong, Yusheng ^a   Tata, Jim ^a   Verras, Andreas ^b   Garcia Calvo, Margarita ^c   Song, Xuelei ^c   Addona, George H ^c   McLaren, Dave G ^c   He, Timothy ^c   Murphy, Beth ^d   Metzger, Dan E ^d   Salituro, Gino ^e   Deckman, Diana ^e   Chen, Qing ^e   Jin, Xiaoling ^f   Stout, Steven J ^g   Wang, Sheng Ping ^g   Wilsie, Larissa ^g   Palyha, Oksana ^g   Han, Seongah ^g   Hubbard, Brian K ^g   Previs, Stephen F ^g   Pinto, Shirly ^g   Taggart, Andrew ^g   more..

^a Department of Discovery Chemistry ^*  (United States)

^b and Informatics   (United States)

^c In Vitro Pharmacology   (United States)

^d In Vivo Pharmacology   (United States)

^e Pharmacokinetics   (United States)

^f Basic Pharmaceutical Sciences   (United States)

^g MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACYLTRANSFERASE INHIBITOR; DIACYLGLYCEROL ACYLTRANSFERASE 2; DIACYLGLYCEROL ACYLTRANSFERASE 2 INHIBITOR; N (TERT BUTYL) 8 [[(TRANS) 2 (3 METHYL 1,2,4 OXADIAZOL 5 YL)CYCLOPROPANECARBOXAMIDE]METHYL] 5 [3 (TRIFLUOROMETHOXY)PHENYL] 3,4 DIHYDROISOQUINOLINE 2 (1H)CARBOXAMIDE; TRIACYLGLYCEROL; UNCLASSIFIED DRUG; DGAT2 PROTEIN, HUMAN; DIACYLGLYCEROL ACYLTRANSFERASE; ENZYME INHIBITOR; ISOQUINOLINE DERIVATIVE;

ANIMAL EXPERIMENT; ARTICLE; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG DISTRIBUTION; DRUG EXCRETION; DRUG HALF LIFE; DRUG METABOLISM; IC50; MOUSE; NONHUMAN; ANIMAL; ANTAGONISTS AND INHIBITORS; BLOOD; C57BL MOUSE; CHEMISTRY; DRUG DEVELOPMENT; HUMAN; MALE; METABOLISM;

ANIMALS; DIACYLGLYCEROL O-ACYLTRANSFERASE; DRUG DISCOVERY; ENZYME INHIBITORS; HUMANS; ISOQUINOLINES; MALE; MICE; MICE, INBRED C57BL; TRIGLYCERIDES;

EID: 84949814601     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.5b01345     Document Type: Article

References (12)

1. Zammit, V. A. Hepatic Triacylglycerol Synthesis and Secretion: DGAT2 as the Link between Glycaemia and Triglyceridaemia Biochem. J. 2013, 451, 1-12 10.1042/BJ20121689
2. Yu, X. X.; Murray, S. F.; Pandey, S. K.; Booten, S. L.; Bao, D.; Song, X. Z.; Kelly, S.; Chen, S.; McKay, R.; Monia, B. P.; Bhanot, S. Antisense Oligonucleotide Reduction of DGAT2 Expression Improves Hepatic Steatosis and Hyperlipidemia in Obese Mice Hepatology 2005, 42, 362-71 10.1002/hep.20783
3. Choi, C. S.; Savage, D. B.; Kulkarni, A.; Yu, X. X.; Liu, Z.-X.; Morino, K.; Kim, S.; Distefano, A.; Samuel, V. T.; Neschen, S.; Zhang, D.; Wang, A.; Zhang, X. M.; Kahn, M.; Cline, G. W.; Pandey, S. K.; Geisler, J. G.; Bhanot, S.; Monia, B. P.; Shulman, G. I. 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, 22678-22688 10.1074/jbc.M704213200
4. Liu, Y.; Millar, J. S.; Cromley, D. A.; Graham, M.; Crooke, R.; Billheimer, J. T.; Rader, D. J. Knockdown of Acyl-CoA:Diacylglycerol acyltransferase 2 with Antisense Oligonucleotide Reduces VLDL TG and ApoB Secretion in Mice Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2008, 1781, 97-104 10.1016/j.bbalip.2008.01.001
5. Song, S. X.; Zhang, J.; Chen, X.; Palyha, O.; Chung, C.; Sonatore, L. M.; Wilsie, L.; Stout, S.; McLaren, D. G.; Taggart, A.; Imbriglio, J. E.; Pinto, S.; Garcia-Calvo, M.; Addona, G. H. Identification of DGAT2 Inhibitors using Mass Spectrometry J. Biomol. Screening 2015, 1-10 10.1177/1087057115607463
6. Wang, J.; Skolnik, S. Permeability Diagnosis Model in Drug Discovery: A Diagnostic Tool to Identify the Most Influencing Properties for Gastrointestinal Permeability Curr. Top. Med. Chem. 2013, 13, 1308-1316 10.2174/15680266113139990035
7. Hopkins, A. L.; Keseru, G. M.; Leeson, P. D.; Rees, D. C.; Reynolds, C. H. The Role of Ligand Efficiency Metrics in Drug Discovery Nat. Rev. Drug Discovery 2014, 13, 105-121 10.1038/nrd4163
8. Bowes, J.; Brown, A. J.; Hamon, J.; Jarolimek, W.; Sridhar, A.; Waldron, G.; Whitebread, S. Reducing Safety Related Drug Attrition: The Use of In Vitro Pharmacological Profiling Nat. Rev. Drug Discovery 2012, 11, 909-922 10.1038/nrd3845
9. Chandler, C. E.; Wilder, D. E.; Pettini, J. L.; Savoy, Y. E.; Petras, S. F.; Chang, G.; Vincent, J.; Harwood, H. J. CP-346086: an MTP Inhibitor that Lowers Plasma Cholesterol and Triglycerides in Experimental Animals and in Humans J. Lipid Res. 2003, 44, 1887-1901 10.1194/jlr.M300094-JLR200
10. Millar, J. S.; Cromley, D. A.; McCoy, M. G.; Rader, D. J.; Billheimer, J. T. Determining Hepatic Triglyceride Production in Mice: Comparison of Poloxamer 407 with Triton WR-1339 J. Lipid Res. 2005, 46, 2023-2028 10.1194/jlr.D500019-JLR200
11. McLaren, D. G.; He, T.; Wang, S.-P.; Mendoza, V.; Rosa, R.; Gagen, K.; Bhat, G.; Herath, K.; Miller, P. L.; Stribling, S.; Taggart, A.; Imbriglio, J.; Liu, J.; Chen, D.; Pinto, S.; Balkovec, J. M.; DeVita, R. J.; Marsh, D. J.; Castro-Perez, J. M.; Strack, A.; Johns, D. J.; Previs, S. F.; Hubbard, B. K.; Roddy, T. P. The Use of Stable-Isotopically Labeled Oleic Acid to Interrogate Lipid Assembly In Vivo: Assessing Pharmacological Effects in Preclinical Species J. Lipid Res. 2011, 52, 1150-1161 10.1194/jlr.M011049
12. During the review of this article, an article was published that discusses the discovery of an imidazopyridine class of DGAT2 inhibitors. Futatsugi, K.; Kung, D. W.; Orr, S. M. T.; Cabral, S.; Hepworth, D.; Aspnes, G.; Bader, S.; Bian, J.; Boehm, M.; Carpino, P. A.; Coffey, S. B.; Dowling, M. S.; Herr, M.; Jiao, W.; Lavergne, S. Y.; Li, Q.; Clark, R. W.; Erion, D. M.; Kou, K.; Lee, K.; Pabst, B. A.; Perez, S. M.; Purkal, J.; Jorgensen, C. C.; Goosen, T. C.; Gosset, J. R.; Niosi, M.; Pettersen, J. C.; Pfefferkorn, J. A.; Ahn, K.; Goodwin, B. Discovery and Optimization of Imidazopyridine-Based Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2) J. Med. Chem. 2015, 58, 7173-7185 10.1021/acs.jmedchem.5b01006