Recent advances in the development of acetyl-CoA carboxylase (ACC) inhibitors for the treatment of metabolic disease

Journal of Medicinal Chemistry

Volumn 58, Issue 2, 2015, Pages 525-536

  Bourbeau, Matthew P ^a   Bartberger, Michael D ^a  

^a AMGEN INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYL COENZYME A CARBOXYLASE INHIBITOR; ENZYME INHIBITOR; UNCLASSIFIED DRUG; ACETYL COENZYME A CARBOXYLASE;

ARTICLE; CHEMICAL STRUCTURE; ENZYME ACTIVITY; ENZYME INHIBITION; FATTY ACID OXIDATION; FATTY ACID SYNTHESIS; HUMAN; METABOLIC DISORDER; METABOLIC PARAMETERS; MOUSE; NONHUMAN; ANIMAL; ANTAGONISTS AND INHIBITORS; BAGG ALBINO MOUSE; CHEMISTRY; DOSE RESPONSE; FEMALE; METABOLIC DISEASES; PROTEIN TERTIARY STRUCTURE; STRUCTURE ACTIVITY RELATION;

ACETYL-COA CARBOXYLASE; ANIMALS; DOSE-RESPONSE RELATIONSHIP, DRUG; ENZYME INHIBITORS; FEMALE; HUMANS; METABOLIC DISEASES; MICE; MICE, INBRED BALB C; PROTEIN STRUCTURE, TERTIARY; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84921525633     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm500695e     Document Type: Article

References (67)

1. Ploakis, S. E.; Guchhait, R. B.; Zwergel, E. E.; Lane, M. D.; Cooper, T. G. Acetyl Coenzyme A Carboxylase System of Escherichia coli: Studies on the Mechanisms of the Biotin Carboxylase and Carboxyltransferase-Catalyzed Reactions J. Biol. Chem. 1974, 249, 6657-6667
2. McGarry, J. D.; Foster, D. W. Regulation of Hepatic Fatty Acid Oxidation and Ketone Body Production Annu. Rev. Biochem. 1980, 49, 395-420
3. Kim, K.-H. Regulation of Mammalian Acetyl-Coenzyme A Carboxylase Annu. Rev. Nutr. 1997, 17, 77-99
4. Bianchi, A.; Evans, J. L.; Iverson, A. J.; Nordlund, A. C.; Watts, T. D.; Witters, L. A. Identification of an Isozymic Form of Acetyl-CoA Carboxylase J. Biol. Chem. 1990, 265, 1502-1509
5. Rasmussen, B. B.; Holmback, U. C.; Volpi, E.; Morio-Liondore, B.; Paddon-Jones, D.; Wolfe, R. R. Malonyl Coenzyme A and the Regulation of Functional Carnitine Palmitoyltransferase-1 Activity and Fat Oxidation in Human Skeletal Muscle J. Clin. Invest. 2002, 110, 1687-1693
6. Zhang, H.; Yang, Z.; Shen, Y.; Tong, L. Crystal Structure of the Carboxyltransferase Domain of Acetyl-Coenzyme A Carboxylase Science 2003, 299, 2064-2067
7. Zhang, H.; Tweel, B.; Tong, L. Molecular Basis for the Inhibition of the Carboxyltransferase Domain of Acetyl-Coenzyme-A Carboxylase by Haloxyfop and Diclofop Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5910-5915
8. Zhang, H.; Tweel, B.; Li, J.; Tong, L. Crystal Structure of the Carboxytransferase Domain of Acetyl-Coenzyme A Carboxylase in Complex with CP-640186 Structure 2004, 12, 1683-1691
9. Xiang, S.; Callaghan, M. M.; Watson, K. G.; Tong, L. A Different Mechanism for the Inhibition of the Carboxytransferase Domain of Acetyl-Coenzyme A Carboxylase by Tepraloxydim Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 20723-20727
10. Yu, L. P. C.; Kim, Y. S.; Tong, L. Mechanism for the Inhibition of the Carboxytransferase Domain of Acetyl-Coenzyme A Carboxylase by Pinoxaden Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 22072-22077
11. Shen, Y.; Volrath, S. L.; Weatherly, S. C.; Elich, T. D.; Tong, L. A Mechanism for the Potent Inhibition of Eukaryotic Acetyl-Coenzyme A Carboxylase by Soraphen A, a Macrocyclic Polyketide Natural Product Mol. Cell 2004, 16, 881-891
12. Abu-Elheiga, L.; Matzuk, M. M.; Abo-Hashema, K. A.; Wakil, S. J. Continuous Fatty Acid Oxidation and Reduced Fat Storage in Mice Lacking Acetyl-CoA Carboxylase 2 Science 2001, 291, 2613-2616
13. Abu-Elheiga, L.; Oh, W.; Kordari, P.; Wakil, S. J. Acetyl-CoA Carboxylase 2 Mutant Mice Are Protected against Obesity and Diabetes Induced by High-Fat/High-Carbohydrate Diets Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 10207-10212
14. Oh, W.; Abu-Elheiga, L.; Kordari, P.; Gu, Z.; Shaikenov, T.; Chirala, S. S.; Wakil, S. J. Glucose and Fat Metabolism in Adipose Tissue of Acetyl-CoA Carboxylase 2 Knockout Mice Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 1384-1389
15. Choi, C. S.; Savage, D. B.; Abu-Elheiga, L.; Zhu, Z. X.; Kim, S.; Kulkarni, A.; Distefano, A.; Hwang, Y. J.; Reznick, R. M.; Codella, R.; Zhang, D.; Cline, G. W.; Wakil, S. J.; Shulman, G. I. Continuous Fat Oxidation in Acetyl-CoA Carboxylase 2 Knockout Mice Increases Total Energy Expenditure, Reduces Fat Mass, and Improves Insulin Sensitivity Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 16480-16485
16. Hoehn, K. L.; Turner, N.; Swarbrick, M. M.; Wilks, D.; Preston, E.; Phua, Y.; Joshi, H.; Furler, S. M.; Larance, M.; Hegarty, B. D.; Leslie, S. J.; Pickford, R.; Hoy, A. J.; Kraegen, E. W.; James, D. E.; Cooney, G. J. Acute or Chronic Upregulation of Mitochondrial Fatty Acid Oxidation Has No Net Effect on Whole-Body Energy Expenditure or Adiposity Cell Metab. 2010, 11, 70-76
17. Olson, D. P.; Pulinilkunnil, T.; Cline, G. W.; Shulman, G. I.; Lowell, B. B. Gene Knockout of Acc2 Has Little Effect on Body Weight, Fat Mass, or Food Intake Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 7598-7603
18. Abu-Elheiga, L.; Matzuk, M. M.; Kordari, P.; Oh, W.; Shaikenov, T.; Gu, Z.; Wakil, S. J. Mutant Mice Lacking Acetyl-CoA Carboxylase 1 Are Embryonically Lethal Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 12011-12016
19. Mao, J.; DeMayo, F. J.; Li, H.; Abu-Elheiga, L.; Gu, Z.; Shaikenov, T.; Kordari, P.; Chirala, S. S.; Heird, W. C.; Wakil, S. J. Liver-Specific Deletion of Acetyl-CoA Carboxylase 1 Reduces Hepatic Triglyceride Accumulation without Affecting Glucose Homeostasis Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 8552-8557
20. Harada, N.; Oda, Z.; Hara, Y.; Fujinama, K.; Okawa, M.; Ohbuchi, K.; Yonemoto, M.; Ikeda, Y.; Ohwaki, K.; Aragane, K.; Tamai, Y.; Kununoki, J. Hepatic De Novo Lipogenesis Is Present in Liver-Specific ACC1-Deficient Mice Mol. Cell. Biol. 2007, 27, 1881-1888
21. Schrauwen, P.; van Aggel-Leijssen, D. P. C.; Hul, G.; Wagenmakers, A. J. M.; Vidal, H.; Saris, W. H. M.; van Baak, M. A. The Effect of a 3-Month Low-Intensity Endurance Training Program on Fat Oxidation and Acetyl-CoA Carboxylase-2 Expression Diabetes 2002, 51, 2220-2226
22. Bandyopadhyay, G. K.; Yu, J. G.; Ofrecio, J.; Olefsky, J. M. Increased Malonyl-CoA Levels in Muscle from Obese and Type 2 Diabetic Subjects Lead to Decreased Fatty Acid Oxidation and Increased Lipogenesis; Thiazolidinedione Treatment Reverses These Defects Diabetes 2006, 55, 2277-2285
23. Musi, N.; Hirshman, M. F.; Nygren, J.; Svanfeldt, S.; Bavenholm, P.; Rooyackers, O.; Zhou, G.; Williamson, J. M.; Ljunqvist, O.; Efendic, S.; Moller, D. E.; Thorell, A.; Goodyear, L. J. Metformin Increases AMP-Activated Protein Kinase Activity in Skeletal Muscle of Subjects with Type 2 Diabetes Diabetes 2002, 51, 2074-2081
24. Corbett, J. W. Review of Recent Acetyl-CoA Carboxylase Inhibitor Patents: Mid-2007-2008 Expert Opin. Ther. Pat. 2009, 19, 943-956
25. Bourbeau, M. P.; Allen, J. G.; Gu, W. Recent Advances in Acetyl- CoA Carboxylase Inhibitors Annu. Rep. Med. Chem. 2010, 45, 95-108
26. Bourbeau, M. P. ACC Inhibitors in Development. In New Therapeutic Strategies for Type 2 Diabetes: Small Molecule Approaches; Jones, R. M., Ed.; Royal Society of Chemistry: Cambridge, U.K., 2012; pp 464-500.
27. Luo, D.-X.; Tong, D.-J.; Rajput, S.; Wang, C.; Liao, D.-F.; Cao, D.; Maser, E. Targeting Acetyl-CoA Carboxylases: Small Molecular Inhibitors and Their Therapeutic Potential Recent Pat. Anti-Cancer Drug Discovery 2012, 7, 168-184
28. Schreurs, M.; van Dijk, T. H.; Gerding, A.; Havinga, R.; Reijngoud, D.-J.; Kuipers, F. Soraphen, an Inhibitor of the Acetyl-CoA Carboxylase System, Improves Peripheral Insulin Sensitivity in Mice Fed a High-Fat Diet Diabetes, Obes. Metab. 2009, 11, 987-991
29. Chonan, T.; Oi, T.; Yamamoto, D.; Yashiro, M.; Wakasugi, D.; Tanaka, H.; Ohoka-Sugita, A.; Io, F.; Koretsune, H.; Hiratate, A. (4-Piperidinyl)-piperazine: A New Platform for Acetyl-CoA Carboxylase Inhibitors Bioorg. Med. Chem. Lett. 2009, 19, 6645-6648
30. Chonan, T.; Tanaka, H.; Yamamoto, D.; Yashiro, M.; Oi, T.; Wakasugi, D.; Ohoka-Sugita, A.; Io, F.; Koretsune, H.; Hiratate, A. Design and Synthesis of Disubstituted (4-Piperidinyl)-piperazine Derivatives as Potent Acetyl-CoA Carboxylase Inhibitors Bioorg. Med. Chem. Lett. 2010, 20, 3965-3968
31. Chonan, T.; Wakasugi, D.; Yamamoto, D.; Yashiro, M.; Oi, T.; Tanaka, H.; Ohoka-Sugita, A.; Io, F.; Koretsune, H.; Hiratate, A. Discovery of Novel (4-Piperidinyl)-piperazines as Potent and Orally Active Acetyl-CoA Carboxylase 1/2 Non-Selective Inhibitors: F-Boc and triF-Boc Groups are Acid-Stable Bioisosteres for the Boc Group Bioorg. Med. Chem. 2011, 19, 1580-1593
32. Keil, S.; Müller, M.; Zoller, G.; Haschke, G.; Schroeter, K.; Glien, M.; Ruf, S.; Focken, I.; Herling, A. W.; Schmoll, D. Identification and Synthesis of Novel Inhibitors of Acetyl-CoA Carboxylase with in Vitro and in Vivo Efficacy on Fat Oxidation J. Med. Chem. 2010, 53, 8679-8687
33. Glien, M.; Haschke, G.; Pfenninger, A.; Zoller, G.; Keil, S.; Müller, M.; Herling, A. W.; Schmoll, D. Stimulation of Fat Oxidation, but No Sustained Reduction of Hepatic Lipids by Prolonged Pharmacological Inhibition of Acetyl CoA Carboxylase Horm. Metab. Res. 2011, 43, 601-606
34. Bengtsson, C.; Blaho, S.; Saitton, D. B.; Brickmann, K.; Broddefalk, J.; Davidsson, Ö.; Drmota, T.; Folmer, R.; Hallberg, K.; Hallén, S.; Hovland, R.; Isin, E.; Johannesson, P.; Kull, B.; Larsson, L.-O.; Löfgren, L.; Nilsson, K. E.; Noeske, T.; Oakes, N.; Plowright, A. T.; Schnecke, V.; Ståhlberg, P.; Sörme, P.; Wan, H.; Wellner, E.; Öster, L. Design of Small Molecule Inhibitors of Acetyl-CoA Carboxylase 1 and 2 Showing Reduction of Hepatic Malonyl-CoA Levels in Vivo in Obese Zucker Rats Bioorg. Med. Chem. 2011, 19, 3039-3053
35. Edwards, M. P.; Price, D. A. Role of Physicochemical Properties and Ligand Lipophilicity Efficiency in Addressing Drug Safety Risks Annu. Rep. Med. Chem. 2010, 45, 381-391
36. Yamashita, T.; Kamata, M.; Endo, S.; Yamamoto, M.; Kakegawa, K.; Watanabe, H.; Miwa, K.; Yamano, T.; Funata, M.; Sakamoto, J.-i.; Tani, A.; Mol, C. D.; Zou, H.; Dougan, D. R.; Sang, B.; Snell, G.; Fukatsu, K. Design, Synthesis, and Structure-Activity Relationships of Spirolactones Bearing 2-Ureidobenzothiophene as Acetyl-CoA Carboxylases Inhibitors Bioorg. Med. Chem. Lett. 2011, 21, 6314-6318
37. Harwood, H. J.; Petras, S. F.; Shelly, L. D.; Zaccaro, L. M.; Perry, D. A.; Makowski, M. R.; Hargrove, D. M.; Martin, K. A.; Tracey, W. R.; Chapman, J. G.; McGee, W. P.; Dalvie, D. K.; Soliman, V. F.; Martin, W. H.; Mularski, C. J.; Eisenbeis, S. A. Isozyme-nonselective N-Substituted Bipiperidylcarboxamide Acetyl-CoA Carboxylase Inhibitors Reduce Tissue Malonyl-CoA Concentrations, Inhibit Fatty Acid Synthesis, and Increase Fatty Acid Oxidation in Cultured Cells and in Experimental Animals J. Biol. Chem. 2003, 278, 37099-37111
38. Madauss, K. P.; Burkhart, W. A.; Consler, T. G.; Cowan, D. J.; Gottschalk, W. K.; Miller, A. B.; Short, S. A.; Tran, T. B.; Williams, S. P. The Human ACC2 CT-Domain C-Terminus Is Required for Full Functionality and Has a Novel Twist Acta Crystallogr., Sect. D 2009, 65, 449-461
39. Kamata, M.; Yamashita, T.; Kina, A.; Funata, M.; Mizukami, A.; Sasaki, M.; Tani, A.; Funami, M.; Amano, N.; Fukatsu, K. Design, Synthesis, and Structure-Activity Relationships of Novel Spiro-Piperidines as Acetyl-CoA Carboxylase Inhibitors Bioorg. Med. Chem. Lett. 2012, 22, 3643-3647
40. Kamata, M.; Yamashita, T.; Kina, A.; Tawada, M.; Endo, S.; Mizukami, A.; Sasaki, M.; Tani, A.; Nakano, Y.; Watanabe, Y.; Furuyama, N.; Funami, M.; Amano, N.; Fukatsu, K. Symmetrical Approach of Spiro-Pyrazolidinediones as Acetyl-CoA Carboxylase Inhibitors Bioorg. Med. Chem. Lett. 2012, 22, 4769-4772
41. Corbett, J. W.; Freeman-Cook, K. D.; Vajdos, R. E. F.; Rajamohan, F.; Kohls, D.; Marr, E.; Zhang, H.; Tong, L.; Tu, M.; Murdande, S.; Doran, S. D.; Houser, J. A.; Song, W.; Jones, C. J.; Coffey, S. B.; Buzon, L.; Minich, M. L.; Dirico, K. J.; Tapley, S.; McPherson, R. K.; Sugarman, E.; Harwood, H. J.; Esler, W. Discovery of Small Molecule Isozyme Non-Specific Inhibitors of Mammalian Acetyl-CoA Carboxylase 1 and 2 Bioorg. Med. Chem. Lett. 2010, 20, 2383-2388
42. Freeman-Cook, K. D.; Amor, P.; Bader, S.; Buzon, L. M.; Coffey, S. B.; Corbett, J. W.; Dirico, K. J.; Doran, S. D.; Elliot, R. L.; Esler, W.; Guzman-Perez, A.; Henegar, K. E.; Houser, J. A.; Jones, C. J.; Limberakis, C.; Loomis, K.; McPherson, K.; Murdande, S.; Nelson, K. L.; Phillion, D.; Pierce, B. S.; Song, W.; Sugarman, E.; Tapley, S.; Tu, M.; Zhao, Z. Maximizing Lipophilic Efficiency: The Use of Free-Wilson Analysis in the Design of Inhibitors of Acetyl-CoA Carboxylase J. Med. Chem. 2012, 55, 935-942
43. Griffith, D. A.; Dow, R. L.; Huard, K.; Edmonds, D. J.; Bagley, S. W.; Polivkova, J.; Zeng, D.; Garcia-Irizarry, C. N.; Southers, J. A.; Esler, W.; Amor, P.; Loomis, K.; McPherson, K.; Bahnck, K. B.; Préville, C.; Banks, T.; Moore, D. E.; Mathiowetz, A. M.; Menhaji-Klotz, E.; Smith, A. C.; Doran, S. D.; Beebe, D. A.; Dunn, M. F. Spirolactam-Based Acetyl-CoA Carboxylase Inhibitors: Toward Improved Metabolic Stability of a Chromanone Lead Structure J. Med. Chem. 2013, 56, 7110-7119
44. Pfizer Pipeline. As of May 8, 2014. http://www.pfizer.com/sites/default/files/product-pipeline/May%208%2C%202014%20Pipeline%20Update-Final-to%20BT.pdf, (accessed Oct, 1, 2014).
45. ClinicalTrials.gov records for PF 05175157. http://clinicaltrials.gov/ct2/results/displayOpt?flds=a&flds=b&flds=f&flds=s&submit-fld-opt=on&term=05175157&show-flds=Y (accessed Oct 1, 2014).
46. The Merck Index Online. Simvastatin. https://www.rsc.org/Merck-Index/monograph/mono1500008677/simvastatin?q=authorize (accessed Oct 1, 2014).
47. The Merck Index Online. Midazolam. https://www.rsc.org/Merck-Index/monograph/mono1500006261/midazolam?q=authorize (accessed Oct 1, 2014).
48. Bagley, S. W.; Southers, J. A.; Cabral, S.; Rose, C. R.; Bernhardson, D. J.; Edmonds, D. J.; Polivkova, J.; Yang, X.; Kung, D. W.; Griffith, D. A.; Bader, S. J. Synthesis of 7-Oxo-dihydrospiro[indazole-5,4′-piperidine] Acetyl-CoA Carboxylase Inhibitors J. Org. Chem. 2012, 77, 1497-1506
49. Huard, K.; Bagley, S. W.; Menhaji-Klotz, E.; Préville, K.; Southers, J. A., Jr.; Smith, A. C.; Edmonds, D. J.; Lucas, J. C.; Dunn, M. F.; Allanson, N. M.; Blaney, E. L.; Garcia-Irizarry, C. N.; Kohrt, J. T.; Griffith, D. A.; Dow, R. L. Synthesis of Spiropiperidine Lactam Acetyl-CoA Carboxylase Inhibitors J. Org. Chem. 2012, 77, 10050-10057
50. Limberakis, C.; Li, J.; Balan, G.; Griffith, D. A.; Kung, D. W.; Rose, C.; Vrieze, D. Complementary α-Alkylation Approaches for a Sterically Hindered Spiro[pyrazolopyranpiperidine]ketone Tetrahedron Lett. 2012, 53, 2543-2547
51. Fleck, M.; Nosse, B.; Heine, N.; Roth, G. J. Azetidine Derivatives. U.S. Patent Application 2013/0158004, 2013.
52. Roth, G. J.; Fleck, M.; Lehmann-Lintz, T.; Nosse, B. Piperidine Derivatives, Pharmaceutical Compositions and Uses Thereof. WO Patent Application 2013/079668, 2013.
53. Roth, G. J.; Fleck, M.; Nosse, B.; Lehmann-Lintz, T. New Piperidine Derivatives, Pharmaceutical Compositions and Uses Thereof. WO Patent Application 2013/092976, 2013.
54. Nosse, B.; Fleck, M.; Roth, G. J.; Heine, N. New Azetidine Derivatives, Pharmaceutical Compositions and Uses Thereof. WO Patent Application 2013/098373, 2013.
55. Fleck, M.; Nosse, B.; Roth, G. J. New Azetidine Derivatives, Pharmaceutical Compositions and Uses Thereof. WO Patent Application 2013/098375, 2013.
56. Marjanovica, J.; Chalupskab, D.; Patenodeb, C.; Costerb, A.; Arnoldb, E.; Yeb, A.; Anesib, G.; Lu, Y.; Okunc, T.; Tkachenkoc, S.; Haselkorna, R.; Gornickib, P. Recombinant Yeast Screen for New Inhibitors of Human Acetyl-CoA Carboxylase 2 Identifies Potential Drugs To Treat Obesity Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 9093-9098
57. Harwood, H. J. Treating the Metabolic Syndrome: Acetyl-CoA Carboxylase Inhibition Expert Opin. Ther. Targets 2005, 9, 267-281
58. Canterbury, D. P.; Scott, C. E. N.; Kubo, O.; Jansen, R.; Cleveland, J. L.; Micalizio, G. C. Synthesis of C11-Desmethoxy Soraphen A1α: A Natural Product Analogue That Inhibits Acetyl-CoA Carboxylase ACS Med. Chem. Lett. 2013, 4, 1244-1248
59. Abel, S.; Faber, D.; Hüter, O.; Giese, B. Total Synthesis of Soraphen A1α Angew. Chem., Int. Ed. 1994, 33, 2466-2468.
60. Abel, S.; Faber, D.; Hüter, O.; Giese, B. Total Synthesis of Soraphen A1α Synthesis 1999, 188-197
61. Trost, B. M.; Sieber, J.; Qian, W.; Dhawan, R.; Ball, Z. T. Asymmetric Total Synthesis of Soraphen A: A Flexible Alkyne Strategy Angew. Chem., Int. Ed. 2009, 48, 5478-5481
62. Harriman, G. C.; Masse, C. E.; Harwood, J.; Bhat, S.; Greenwood, J. R. ACC Inhibitors and Uses Thereof. WO Patent Application 2013/071169, 2013.
63. Harriman, G. C.; Greenwood, J. R.; Bhat, S.; Kapeller, R.; Harwood, H. J. Acetyl-CoA Carboxylase Inhibition by NDI-630 Inhibits Fatty Acid Synthesis, Stimulates Fatty Acid Oxidation, Reduces Body Weight, Improves Insulin Sensitivity, and Modulates Dyslipidemia in Rats. Presented at the 73rd Annual Scientific Sessions of the American Diabetes Association, 2013; Abstract 636-P.
64. DePeralta, D. K.; Wei, L.; Harriman, G.; Greenwood, J.; Bhat, S.; Westlin, W.; Harwood, H. J., Jr.; Kapeller, R.; Tanabe, K. K.; Fuchs, B. C. Liver Selective Acetyl-CoA Carboxylase Inhibition by ND-654 Decreases Hepatocellular Carcinoma Development in Cirrhotic Rats. Presented at the 105th Annual Meeting of the American Association for Cancer Research, 2014; Abstract 1427.
65. Svensson, R. U.; Harriman, G.; Greenwood, J.; Bhat, S.; Harwood, H. J., Jr.; Kapeller, R.; Shaw, R. J. Acetyl-CoA Carboxylase Inhibition by ND646 Reduces Fatty Acid Synthesis and Inhibits Cell Proliferation in Human Non-Small Cell Clung Cancer Cells. Presented at the 105th Annual Meeting of the American Association for Cancer Research, 2014; Abstract 2679.
66. Bourbeau, M. P.; Siegmund, A.; Allen, J. G.; Shu, H.; Fotsch, C.; Bartberger, M. D.; Kim, K.-W.; Komorowski, R.; Graham, M.; Busby, J.; Wang, M.; Meyer, J.; Xu, Y.; Salyers, K.; Fielden, M.; Véniant, M. M.; Gu, W. Piperazine Oxadiazole Inhibitors of Acetyl-CoA Carboxylase J. Med. Chem. 2013, 56, 10132-10141
67. Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success J. Med. Chem. 2009, 52, 6752-6756