Potent DGAT1 inhibitors in the benzimidazole class with a pyridyl-oxy-cyclohexanecarboxylic acid moiety

ACS Medicinal Chemistry Letters

Volumn 4, Issue 8, 2013, Pages 773-778

  He, Shuwen ^a   Hong, Qingmei ^a   Lai, Zhong ^a   Wu, Zhicai ^a   Yu, Yang ^a   Kim, David W ^a   Ting, Pauline C ^a   Kuethe, Jeffrey T ^a   Yang, Ginger X ^a   Jian, Tianying ^a   Liu, Jian ^a   Guiadeen, Deodial ^a   Krikorian, Arto D ^a   Sperbeck, Donald M ^a   Sonatore, Lisa M ^a   Wiltsie, Judyann ^a   Chung, Christine C ^a   Gibson, Jack T ^a   Lisnock, Jeanmarie ^a   Murphy, Beth A ^a   Gorski, Judith N ^a   Liu, Jinqi ^a   Chen, Dunlu ^a   Chen, Xiaoli ^a   Wolff, Michael ^a   Tong, Sharon X ^a   Madeira, Maria ^a   Karanam, Bindhu V ^a   Shen, Dong Ming ^a   Balkovec, James M ^a   Pinto, Shirly ^a   Nargund, Ravi P ^a   DeVita, Robert J ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

ACAT1; benzimidazole; cyclohexanecarboxylic acid; DGAT1; epimerization; inhibitor; lipid tolerance test; metabolite

Indexed keywords

ABT 046; AZD 7687; BENZIMIDAZOLE; CYCLOHEXANECARBOXYLIC ACID DERIVATIVE; DIACYLGLYCEROL ACYLTRANSFERASE 1; DIACYLGLYCEROL ACYLTRANSFERASE 1 INHIBITOR; LCQ 908; PF 4620110; TRIACYLGLYCEROL; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; CHEMISTRY; CONTROLLED STUDY; DOG; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DESIGN; DRUG EFFICACY; DRUG SELECTIVITY; DRUG SYNTHESIS; EPIMERIZATION; FAT TOLERANCE TEST; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HUMAN; IC 50; IN VIVO STUDY; INTESTINE; MAXIMUM PLASMA CONCENTRATION; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROPENSITY SCORE; SCALE UP; SUZUKI REACTION; TIME TO MAXIMUM PLASMA CONCENTRATION;

CANIS FAMILIARIS; MUS;

EID: 84881426974     PISSN: None     EISSN: 19485875     Source Type: Journal    
DOI: 10.1021/ml400168h     Document Type: Article

References (31)

1. Scully, T. Diabetes in numbers Nature 2012, 485, S2-S3
2. World Health Organization (WHO). Fact sheet No. 311. Obesityand overweight. Updated March (2013. Available at: http://www.who.int/mediacentre/ factsheets/fs311/en/.
3. Flegal, K. M.; Carroll, M. D.; Kit, B. K.; Ogden, C. L. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010 J. Am. Med. Assoc. 2012) 307, 491-497
4. Guariguata, L. By the numbers: new estimates from the IDF Diabetes Atlas Update for 2012 Diabetes Res. Clin. Pract. 2012, 98, 524-525
5. For a recent review on pharmacologic treatment for Type-2 diabetes, see: Morsink, L. M.; Smits, M. M.; Diamant, M. Advances in pharmacologic therapies for type 2 diabetes Curr. Atheroscler. Rep. 2013, 15, 302
6. Moller, D. E. Metabolic disease drug discovery: "Hitting the target" is easier said than done Cell Metab. 2012, 15, 19-24
7. Zhang, Z.-Y.; Wang, M.-W. Obesity, a health burden of a global nature Acta Pharmacol. Sin. 2012, 33, 145-147
8. King, A. J.; Judd, A. S.; Souers, A. J. Inhibitors of diacylglycerol acyltransferase: a review of 2008 patents Exp. Opin. Ther. Patents 2010, 20, 19-29
9. 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
10. Cases, S.; Smith, S. J.; Zheng, Y.-W.; Myers, H. M.; Lear, S. R.; Sande, E.; Novak, S.; Collins, C.; Welch, C. B.; Lusis, A. J.; Erickson, S. K.; Farese, R. V., Jr. Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis Proc. Natl. Acad. Sci. 1998, 95, 13018-13023
11. Cases, S.; Stone, S. J.; Zhou, P.; Yen, E.; Tow, B.; Lardizabal, K. D.; Voelker, T.; Farese, R. V., Jr. Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members J. Biol. Chem. 2001, 276, 38870-38876
12. Pramfalk, C.; Eriksson, M.; Parini, P. Cholesteryl esters and ACAT Eur. J. Lipid Sci. Technol. 2012, 114, 624-633
13. 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
14. 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
15. For recent reports of DGAT1 inhibitors, see: 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. Abstracts of Papers, 243rd ACS National Meeting & Exposition, San Diego, CA, March 25-29, 2012.
16. 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 DGAT-1 ACS Med. Chem. Lett. 2011, 2, 407-412
17. Yeh, V. S.; Beno, D. W.; Brodjian, S.; Brune, M. E.; Cullen, S. C.; Dayton, B. D.; Dhaon, M. K.; Falls, H. D.; Gao, J.; Grihalde, N.; Hajduk, P.; Hansen, T. M.; Judd, A. S.; King, A. J.; Klix, R. C.; Larson, K. J.; Lau, Y. Y.; Marsh, K. C.; Mittelstadt, S. W.; Plata, D.; Rozema, M. J.; Segreti, J. A.; Stoner, E. J.; Voorbach, M. J.; Wang, X.; Xin, X.; Zhao, G.; Collins, C. A.; Cox, B. F.; Reilly, R. M.; Kym, P. R.; Souers, A. J. Identification and preliminary characterization of a potent, safe, and orally efficacious inhibitor of acyl-CoA:diacylglycerol acyltransferase 1 J. Med. Chem. 2012, 55, 1751-1757
18. 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.; Johansson, M. J.; Kemmitt, P. D.; Lindmark, B. T.; Morentin, G. P.; Noesk, 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
19. Waring, M. J.; Birch, A. M.; Birtles, S.; Buckett, L. K.; Butlin, R. J.; Campbell, L.; Gutierrez, P. M.; Kemmitt, P. D.; Leach, A. G.; MacFaul, P. A.; O'Donnell, C.; Turnbull, A. V. Optimisation of biphenyl acetic acid inhibitors of diacylglycerol acetyl transferase 1: the discovery of AZD2353 Med. Chem. Commun. 2013, 4, 159-164
20. Goldberg, F. W.; Birch, A. M.; Leach, A. G.; Groombridge, S. D.; Snelson, W. L.; Gutierrez, P. M.; Hammond, C. D.; Birtles, S.; Buckett, L. K. Discovery and optimization of efficacious neutral 4-amino-6-biphenyl-7,8- dihydropyrimido[5,4-f][1,4]oxazepin-5-one diacylglycerol acyl transferase-1 (DGAT1) inhibitors Med. Chem. Commun. 2013, 4, 165-174
21. Liu, J. Pharmacological inhibition of diacylglycerol acyltransferase 1 reduces body weight and modulates gut peptide release: potential insight into mechanism of action Obesity 2013, 10.1002/oby.20193
22. Lin, H. V.; Chen, D.; Shen, Z.; Zhu, L.; Ouyang, X.; Vongs, A.; Kan, Y.; Levorse, J. M.; Kowalik, E. J.; Szeto, D. M.; Yao, X.; Xiao, J.; Chen, S.; Liu, J.; Garcia-Calvo, M.; Shin, M. K.; Pinto, S. Diacylglycerol acyltransferase-1 (DGAT1) inhibition perturbs postprandial gut hormone release PLoS One 2013, 8, e54480 10.1371/journal.pone.0054480
23. This structure class was a hybrid of the known acid series and a HTS (high throughput screening) hit containing a benzimidazole moiety. Liu, J. Discovery of 2-biarylbenzimidazoles as novel DGAT1 inhibitors. Poster presented at 33rd National Medicinal Chemistry Symposium, Tucson, AZ, May 20-13, 2012
24. Inhibition of ACAT has been shown to cause adverse changes in preclinical species, see: Floettmann, J. E.; Buckett, L. K.; Turnbull, A. V.; Smith, T.; Hallberg, C.; Birch, A.; Lees, D.; Jones, H. B. ACAT-selective and nonselective DGAT1 inhibition: Adrenocortical effects-a cross-species comparison Toxicol. Pathol. 2013, 10.1177/0192623313477753
25. After our work in the series was completed, an interesting report appeared recently in the literature describing DGAT1 inhibitors in the oxadiazole amide series containing this pyridyl-oxy-cyclohexanecarboxylic acid side chain: Plowright, A. T.; Barton, P.; Stuart, B.; Alan, M.; Birtles, S.; Buckett, L. K.; Butlin, R. J.; Davies, R. D. M.; Ertan, A.; Gutierrez, P. M.; Kemmitt, P. D.; Leach, A. G.; Svensson, P. H.; Turnbull, A. V.; Waring, M. J. Design and synthesis of a novel series of cyclohexyloxy-pyridyl derivatives as inhibitors of diacylglycerol acyl transferase 1 Med. Chem. Commun. 2013, 4, 151-158
26. For the reaction condition forming benzimidazole: Beaulieu, P. L.; Haché, B.; von Moos, E. A practical Oxone®-mediated, high-throughput, solution-phase synthesis of benzimidazoles from 1,2-phenylenediamines and aldehydes and its application to preparative scale synthesis Synthesis 2003, 11, 1683-1692
27. Jones, D. A.; Nongrum, F. M. Intramolecular Diels-Alder additions to 2-benzopyran-3-ones; endo-selective additions and some reactions of the adducts J. Chem. Soc., Perkin Trans. 1 1996, 705-713
28. Intestine targeted DGAT1 inhibitors were recently reported: Serrano-Wu, M. H.; Coppola, G. M.; Gong, Y.; Neubert, A. D.; 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
29. Sanins, S. M.; Adams, W. J.; Kaiser, D. G.; Halstead, G. W.; Hosley, J.; Barnes, H.; Baillie, T. A. Mechanistic studies on the metabolic chiral inversion of R-ibuprofen in the rat Drug Metab. Dispos. 1991, 19, 405-10
30. Knihinicki, R. D.; Williams, K. M.; Day, R. O. Chiral inversion of 2-arylpropionic acid nonsteroidal anti-inflammatory drugs. 1. In vitro studies of ibuprofen and flurbiprofen Biochem. Pharmacol. 1989, 38, 4389-95
31. Center for Drug Evaluation and Research, U.S. FDA. Guidancefor Industry: Safety Testing of Drug Metabolites, February 2008. http://www.fda.gov/downloads/ Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079266.pdf (downloaded April 2013).