Current status of the research and development of diacylglycerol o -acyltransferase 1 (DGAT1) inhibitors

Journal of Medicinal Chemistry

Volumn 56, Issue 24, 2013, Pages 9820-9825

  Devita, Robert J ^b   Pinto, Shirly ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

^b RJD Medicinal Chemistry   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACYLTRANSFERASE INHIBITOR; AZD 7687; DIACYLGLYCEROL ACYLTRANSFERASE 1; DIACYLGLYCEROL ACYLTRANSFERASE 1 INHIBITOR; HEMOGLOBIN A1C; JTT 553; METFORMIN; PF 04620110; PRADIGASTAT; TRIACYLGLYCEROL; UNCLASSIFIED DRUG;

AREA UNDER THE CURVE; DIARRHEA; DOSE RESPONSE; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DOSE COMPARISON; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG METABOLISM; DRUG POTENCY; DRUG RESEARCH; DRUG STABILITY; DRUG STRUCTURE; HALF LIFE TIME; HUMAN; HYPERLIPOPROTEINEMIA TYPE 1; HYPERTRIGLYCERIDEMIA; LOW DRUG DOSE; LOW FAT DIET; MAXIMUM PLASMA CONCENTRATION; NAUSEA; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); REVIEW; TIME TO MAXIMUM PLASMA CONCENTRATION; UNSPECIFIED SIDE EFFECT; VOMITING;

EID: 84889100046     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm4007033     Document Type: Review

References (26)

1. Dow, R. L. Acyl-CoA: Diacylglycerol Acyl Transferase 1 Inhibition as an Approach to the Treatment of Type II Diabetes. In New Therapeutic Strategies for Type 2 Diabetes: Small Molecule Approaches; Jones, R. M., Ed.; Royal Society of Chemistry Publishing: Cambridge, U.K., 2012; pp 215-248.
2. Birch, A. M.; Buckett, L. K.; Turnbull, A. V. DGAT1 inhibitors as anti-obesity and anti-diabetic agents Curr. Opin. Drug Discovery Dev. 2010, 13, 489-496
3. Matsuda, D.; Tomoda, H. DGAT inhibitors for obesity Curr. Opin. Invest. Drugs 2007, 8, 836-841
4. Smith, S. J.; Cases, S.; Jensen, D. R.; Chen, H. C.; Sande, E.; Tow, B.; Sanan, D. A.; Raber, J.; Eckel, R. H.; Farese, R. V., Jr. Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking DGAT Nat. Genet. 2000, 25, 87-90
5. Chen, H. C.; Smith, S. J.; Ladha, Z.; Jensen, D. R.; Ferreira, L. D.; Pulawa, L. K.; McGuire, J. G.; Pitas, R. E.; Eckel, R. H.; Farese, R. V., Jr. Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1 J. Clin. Invest. 2002, 109, 1049-1055
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, 377-381
7. Herker, E.; Harris, C.; Hernandez, C.; Carpentier, A.; Kaehlcke, K.; Rosenberg, A. R.; Farese, R. V., Jr.; Ott, M. Efficient hepatitis C virus particle formation requires diacylglycerol acyltransferase-1 Nat. Med. 2010, 16, 1295-1298
8. Birch, A. M.; Birtles, S.; Buckett, L. K.; Kemmitt, P. D.; Smith, G. J.; Smith, T. J.; Turnbull, A. V.; Wang, S. J. Discovery of a potent, selective, and orally efficacious pyrimidinooxazinyl bicyclooctaneacetic acid diacylglycerol acyltransferase1inhibitors J. Med. Chem. 2009, 52, 1558-1568
9. Liu, J.; Gorski, J.; Gold, S. J.; Chen, D.; Chen, S.; Forrest, G.; Itoh, Y.; Marsh, D. J.; McLaren, D. J.; Shen, Z.; Sonatore, L.; Carballo-Jane, E.; Craw, S.; Guan, X.; Karanam, B.; Sakaki, J.; Szeto, D.; Tong, X.; Xiao, J.; Yoshimoto, R.; Yu, H.; Balkovec, J.; Pinto, S. Pharmacological inhibition of diacylglycerol acyltransferase 1 reduces body weight and modulates gut peptide release-potential insight into mechanism of action Obesity 2013, 21, 1406-1415
10. Maciejewski, B. S.; LaPerle, J. L.; Chen, D.; Ghosh, A.; Zavadoski, W. J.; McDonald, T. S.; Manion, T. B.; Mather, D.; Patterson, T. A.; Hanna, M.; Watkins, S.; Gibbs, E. M.; Calle, R. A.; Steppan, C. M. Pharmacological inhibition to examine the role of DGAT1 in dietary lipid absorption in rodents and humans Am. J. Physiol.: Gastrointest. Liver Physiol. 2013, 304, G958-G969
11. Fox, B. M.; Furukawa, N.; Hao, X.; Iio, K.; Inaba, T.; Jackson, S. M.; Kayser, F.; Labelle, M.; Li, K.; Matsui, T.; McMinn, D. L.; Ogawa, N.; Rubenstein, S. M.; Sagawa, S.; Sugimoto, K.; Suzuki, M.; Tanaka, M.; Ye, G.; Yoshida, A.; Zhang, J. WO2004/047755A2, 2004; U.S. Patent Application US 2004/0209871 A1, 2004.
12. Cao, J.; Zhou, Y.; Peng, H.; Huang, X.; Stahler, S.; Suri, V.; Qadri, A.; Gareski, T.; Jones, J.; Hahm, S.; Perreault, M.; McKew, J.; Shi, M.; Xu, X.; Tobin, J. F.; Gimeno, R. E. Targeting Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) with small molecule inhibitors for the treatment of metabolic diseases J. Biol. Chem. 2011, 286, 41838-41851
13. Dow, R. L.; Li, J. C.; Pence, M. P.; Gibbs, E. M.; LaPerle, J. L.; Litchfield, J.; Piotrowski, D. W.; Munchhof, M. J.; Manion, T. B.; Zavadoski, W. J.; Walker, G. S.; McPherson, R. K.; Tapley, S.; Sugarman, E.; Guzman-Perez, A.; DaSilva-Jardine, P. Discovery of PF-04620110, a potent, selective, and orally bioavailable inhibitor of DGAT1 ACS Med. Chem. Lett. 2011, 2, 407-412
14. Barlind, J. G.; Bauer, U. A.; Birch, A. M.; Birtles, S.; Buckett, L. K.; Butlin, R. J.; Davies, R. D. M.; Eriksson, J. W.; Hammond, C. D.; Hovland, R.; Johannesson, P.; Johanson, M. J.; Kemmitt, P. D.; Lindmark, B. T.; Morentin Gutierrez, P.; Noeske, T. A.; Nordin, A.; O'Donnell, C. J.; Petersson, A. U.; Redzic, A.; Turnbull, A,V.; Vinblad, J. Design and optimization of pyrazinecarboxamide-based inhibitors of diacylglycerol acyltransferase 1 (DGAT1) leading to a clinical candidate dimethylpyrazinecarboxamide phenylcyclohexylacetic acid (AZD7687) J. Med. Chem. 2012, 55, 10610-10629
15. McCoull, W.; Addie, M. S.; Birch, A. M.; Birtles, S.; Buckett, L. K.; Butlin, R. J.; Bowker, S. S.; Boyd, S.; Chapman, S.; Davies, R. D. M.; Donald, C. S.; Green, C. P.; Jenner, C.; Kemmitt, P. D.; Leach, A. G.; Moody, G. C.; Morentin Gutierrez, P.; Newcombe, N. J.; Nowak, T.; Packer, M. J.; Plowright, A. T.; Revill, J.; Schofield, P.; Sheldon, C.; Stokes, S.; Turnbull, A. V.; Wang, S. J. Y.; Whalley, D. P.; Wood, J. M. Identification, optimization and in vivo evaluation of oxadiazole DGAT1 inhibitors for the treatment of obesity and diabetes Bioorg. Med. Chem. Lett. 2012, 22, 3873-3878
16. Serrano-Wu, M. H.; Kwak, Y.; Coppola, G.; Foster, C.; Gilmore, T.; Gong, Y.; He, G.; Hou, Y.; Kantor, A.; Li, J.; Mergo, W.; Nakajima, K.; Neubert, A.; Radetich, B.; Stroup, B.; Sung, M.; Szklennik, P.; Tichkule, R.; Yang, L.; Yoon, T.; Zhu, Y.; Wareing, J.; Hosagrahara, V.; Jain, M.; Chatelain, R.; Commerford, R.; Dardik, B.; Meyers, D.; Hubbard, B. Discovery of a DGAT1 Inhibitor with Robust Suppression of Postprandial Triglyceride Levels in Humans. Presented at the 243rd National Meeting of the American Chemical Society, San Diego, CA, March 26, 2012; Session "Diacylglycerol Acyltransferase 1 (DGAT1) and Metabolic Diseases", MEDI 230.
17. Serrano-Wu, M. H.; Coppola, G.; Gong, Y.; Neubert, A.; Chatelain, R.; Clairmont, K. B.; Commerford, R.; Cosker, T.; Daniels, T.; Hou, Y.; Jain, M.; Juedes, M.; Li, L.; Mullarkey, T.; Rocheford, E.; Sung, M. J.; Tyler, A.; Yang, Q.; Yoon, T.; Hubbard, B. K. Intestinally targeted diacylglycerol acyltransferase 1 (DGAT1) inhibitors robustly suppress postprandial triglycerides ACS Med. Chem. Lett. 2012, 3, 411-415
18. Hagmann, W. K. The many roles for fluorine in medicinal chemistry J. Med. Chem. 2008, 51, 4359-4369
19. Serrano-Wu, M. H. Manuscripts describing the design and SAR of LCQ908 are in preparation; unpublished results.
20. ClinicalTrials.gov for PF-04620110. http://clinicaltrials.gov/ct2/ results?term=PF-04620110&Search=Search.
21. Denison, H.; Nilsson, C.; Kujacic, M.; Lofgren, L.; Karlsson, C.; Knutsson, M.; Eriksson, J. W. Proof of mechanism for the DGAT1 inhibitor AZD7687: results from a first-time-in-human single dose study Diabetes, Obes. Metab. 2013, 15, 136-143
22. Drucker, D. J. Development of glucagon-like peptide-1-based pharmaceuticals as therapeutic agents for the treatment of diabetes Curr. Pharm. Des. 2001, 7, 1399-1412
23. Novartis. Clinical Trial Results Database. http://www.novctrd.com/ ctrdWebApp/clinicaltrialrepository/displayFile.do?trialResult=4314.
24. Meyers, C.; Gaudet, D.; Tremblay, K.; Amer, A.; Chen, J.; Aimin, F. The DGAT1 inhibitor LCQ908 decreases triglyceride levels in patients with the familial chylomicronemia syndrome J. Clin. Lipidol. 2012, 6, 266-267
25. Novartis Clinical Trial Results Database. http://www.novctrd.com/ ctrdWebApp/clinicaltrialrepository/displayFile.do?trialResult=8064.
26. Haas, J. T.; Winter, H. S.; Lim, E.; Kirby, A.; Blumenstiel, B.; DeFelice, M.; Gabriel, S.; Jalas, C.; Branski, D.; Grueter, C. A.; Toporovski, M. S.; Walther, T. C.; Daly, M. J.; Farese, R. V., Jr. DGAT1 mutation is linked to a congenital diarrheal disorder J. Clin. Invest. 2012, 122, 4680-4684