Increased Intrahepatic Triglyceride Is Associated with Peripheral Insulin Resistance: In Vivo MR Imaging and Spectroscopy Studies
Hwang, J.-H.; Stein, D. T.; Barzilai, N.; Cui, M.-H.; Tonelli, J.; Kishore, P.; Hawkins, M. Increased Intrahepatic Triglyceride Is Associated with Peripheral Insulin Resistance: In Vivo MR Imaging and Spectroscopy Studies Am. J. Physiol.: Endocrinol. Metab. 2007, 293, E1663-E1669
Liver, Muscle, and Adipose Tissue Insulin Action Is Directly Related to Intrahepatic Triglyceride Content in Obese Subjects
Korenblat, K. M.; Fabbrini, E.; Mohammed, B. S.; Klein, S. Liver, Muscle, and Adipose Tissue Insulin Action Is Directly Related to Intrahepatic Triglyceride Content in Obese Subjects Gastroenterology 2008, 134, 1369-1375
Continuous Fat Oxidation in Acetyl-CoA Carboxylase 2 Knockout Mice Increases Total Energy Expenditure, Reduces Fat Mass, and Improves Insulin Sensitivity
Choi, C. S.; Savage, D. B.; Abu-Eleiga, L.; Liu, 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
Reversal of Diet-Induced Hepatic Steatosis and Hepatic Insulin Resistance by Antisense Oligonucleotide Inhibitors of Acetyl-CoA Carboxylases 1 and 2
Savage, D. B.; Choi, C. S.; Samuel, V. T.; Liu, Z.-X.; Zhang, D.; Wang, A.; Zhang, X.-M.; Cline, G. W.; Yu, X. X.; Geisler, J. G.; Bhanot, S.; Monia, B. P.; Shulman, G. I. Reversal of Diet-Induced Hepatic Steatosis and Hepatic Insulin Resistance by Antisense Oligonucleotide Inhibitors of Acetyl-CoA Carboxylases 1 and 2 J. Clin. Invest. 2006, 116, 817-824
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
Harwood, H. J., Jr.; 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.; Magee, 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
Soraphen, an Inhibitor of the Acetyl-CoA Carboxylase System, Improves Peripheral Insulin Sensitivity in Mice Fed a High-Fat Diet
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
Modulation of Fatty Acid Metabolism as a Potential Approach to the Treatment of Obesity and the Metabolic Syndrome
Kusunoki, J.; Kanatani, A.; Moller, D. E. Modulation of Fatty Acid Metabolism as a Potential Approach to the Treatment of Obesity and the Metabolic Syndrome Endocrine 2006, 29, 91-100
Discovery of Small Molecule Isozyme Non-Specific Inhibitors of Mammalian Acetyl-CoA Carboxylase 1 and 2
Corbett, J. W.; Freeman-Cook, K. D.; Elliott, R.; Vajdos, 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., Jr.; 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
Maximizing Lipophilic Efficiency: The Use of Free-Wilson Analysis in the Design of Inhibitors of Acetyl-CoA Carboxylase
Freeman-Cook, K. D.; Amor, P.; Bader, S.; Buzon, L. M.; Coffey, S. B.; Corbett, J. W.; Dirico, K. J.; Doran, S. D.; Elliott, R. L.; Esler, W.; Guzman-Perez, A.; Henegar, K. E.; Houser, J. A.; Jones, C. S.; Limberakis, C.; Loomis, K.; McPherson, K.; Murdande, S.; Nelson, K. L.; Phillion, D.; Pierce, B. S.; 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
Role of Physicochemical Properties and Ligand Lipophilicity Efficiency in Addressing Drug Safety Risks
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, 380-391
Development of a New Permeability Assay Using Low-Efflux MDCKII Cells
Di, L.; Whitney-Pickett, C.; Umland, J. O.; Zhang, H.; Zhang, X.; Gebhard, D. F.; Lai, Y.; Federico, J. J.; Davidson, R. E.; Smith, R.; Reyner, E. L.; Lee, C.; Feng, B.; Rotter, C.; Varma, M. V.; Kempshall, S.; Fenner, K.; El-Kattan, A. F.; Liston, T. E.; Troutman, M. D. Development of a New Permeability Assay Using Low-Efflux MDCKII Cells J. Pharm. Sci. 2011, 100, 4974-4985
Eng, H.; Niosi, M.; Tan, B.; Doran, S.; Garcia-Irizarry, C. N.; Griffith, D. A.; Kalgutkar, A. S.; Kung, D. W.; Esler, W.; Steidl, J.
Eng, H.; Niosi, M.; Tan, B.; Doran, S.; Garcia-Irizarry, C. N.; Griffith, D. A.; Kalgutkar, A. S.; Kung, D. W.; Esler, W.; Steidl, J.
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Complementary α-Alkylation Approaches for a Sterically Hindered Spiro[pyrazolopyranpiperidine]ketone
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
A New Amine Catalyzed Synthesis of 2-Substituted 2,3-Dihydro-4H-1,3- benzoxazin-4-ones
Compound 2 was prepared by condensation of N-protected 4-piperidinone with salicylamide under previously reported conditions
Compound 2 was prepared by condensation of N-protected 4-piperidinone with salicylamide under previously reported conditions: Gammill, R. B. A New Amine Catalyzed Synthesis of 2-Substituted 2,3-Dihydro-4H-1,3-benzoxazin-4-ones J. Org. Chem. 1981, 46, 3340-3342
For examples of aminal ACC inhibitors, see: U.S. Patent US20100009982
For examples of aminal ACC inhibitors, see: Anderson, R.; Breazeale, S.; Elich, T.; Lee, S.-F. Modulators of acetyl-coenzyme A carboxylase and methods of use thereof. U.S. Patent US20100009982, 2010.
Synthesis of Spiropiperidine Lactam Acetyl-CoA Carboxylase Inhibitors
For experimental details and synthesis of compounds 5, 11, 12, and 31, see Huard, K.; Bagley, S. W.; Menhaji-Klotz, E.; Préville, C.; Southers, J. A.; 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
Novel Indazole Non-Nucleoside Reverse Transcriptase Inhibitors Using Molecular Hybridization Based on Crystallographic Overlays
Compound 6 was tested for cytochrome P450 time-dependant inhibition at 60 μM in human liver microsomes and caused a 38% decrease activity of CYP3A4 after 30 minutes of incubation, as determined by midazolam metabolism. Other examples of formation of reactive metabolites associated with 3-methylindazole scaffold were previously reported in the literature
Compound 6 was tested for cytochrome P450 time-dependant inhibition at 60 μM in human liver microsomes and caused a 38% decrease activity of CYP3A4 after 30 minutes of incubation, as determined by midazolam metabolism. Other examples of formation of reactive metabolites associated with 3-methylindazole scaffold were previously reported in the literature: Jones, L. H.; Allan, G.; Barba, O.; Burt, C.; Corbau, R.; Dupont, T.; Knöchel, T.; Irving, S.; Middleton, D. S.; Mowbray, C. E.; Perros, M.; Ringrose, H.; Swain, N. A.; Webster, R.; Westby, M.; Phillips, C. Novel Indazole Non-Nucleoside Reverse Transcriptase Inhibitors Using Molecular Hybridization Based on Crystallographic Overlays J. Med. Chem. 2009, 52, 1219-1223
The synthesis of 2′-isopropyl-4′,6′- dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H) -one hydrochloride salt (32), 2′-cyclobutyl-4′,6′- dihydrospiro[piperidine-4,5′-pyrazolo[3,4- c ]pyridin]-7′(2′ H)-one hydrochloride salt (33), 2′- tert -pentyl-4′,6′- dihydrospiro[piperidine-4,5′-pyrazolo[3,4- c ]pyridin]-7′(2′ H)-one hydrochloride salt (34), 1′- tert -butyl-4′,6′- dihydrospiro[piperidine-4,5′-pyrazolo[3,4- c ]-7′(1′ H)-one hydrochloride salt (35), 6-bromo-3-methoxyisoquinoline (41), and 2-(methylamino)quinoline-7-carboxylic acid was previously described in the literature: Bagley, S. W.; Dow, R. L.; Griffith, D. A.; Smith, A. C. N1/N2-Lactam Acetyl-CoA Carboxylase Inhibitors. International Patent WO12056372; 2012.
