5456 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22
Ebdrup et al.
(20) Wang, S. P.; Laurin, N.; Himms-Hagen, J.; Rudnicki, M. A.; Levy,
E.; Robert, M.-F.; Pan, L.; Oligny, L.; Mitchell, G. A. Α. The adipose
tissue phenotype of hormone-sensitive lipase deficiency in mice.
Obes. Res. 2001, 9, 119-128.
(21) Okazaki, H.; Osuga, J.-I.; Tamura, Y.; Yahagi, N.; Tomita, S.;
Shionoiri, F.; Iizuka, Y.; Ohashi, K.; Harada, K.; Kimura, S.; Gotoda,
T.; Shimano, H.; Yamada, N.; Ishibashi, S. Lipolysis in the absence
of hormone-sensitive lipase: Evidence for a common mechanism
regulating distinct lipases. Diabetes 2002, 51, 3368-3375.
(22) Haemmerle, G.; Zimmermann, R.; Hayn, M.; Theussl, C.; Waeg,
G.; Wagner, E.; Sattler, W.; Magin, T. M.; Wagner, E. F.; Zechner,
R. Hormone-sensitive lipase deficiency in mice causes diglyceride
accumulation in adipose tissue, muscle, and testis. J. Biol. Chem.
2002, 277, 4806-4815.
an average concentration of CYP subtypes, which is known to differ
markedly between individuals.
The metabolic conversion of [O-methyl-14C]-dextromethorphan,
[N-methyl-14C]erythromycin, or [O-ethyl-14C]phenacetin, respec-
tively, were assessed by activated charcoal extraction, followed by
liquid scintillation counting of the supernatant. The thereby
measured 14C-formaldehyde reflected the metabolism of the selec-
tive substrate by CYP subtype.
Acknowledgment. The technical assistance from Aase
Vinterby, Johnny Madsen, Lotte Gottlieb Sørensen, Helle Bach,
and Freddy Z. Pedersen are highly appreciated.
(23) Zimmermann, R.; Strauss, J. G.; Haemmerle, G.; Schoiswohl, G.;
Birner-Gruenberger, R.; Riederer, M.; Lass, A., Neuberger, G.;
Eisenhaber, F.; Hermetter, A.; Zechner, R. Fat mobilisation in adipose
tissue is promoted by adipose triglyceride lipase. Science 2004, 306,
1383-1386.
(24) Lowe, D. B. In vitro SAR of (5-2H)-isoxazolonyl)ureas, potent
inhibitors of hormone-sensitive lipase. Bioorg. Med. Chem. Lett. 2004,
14, 3155-3159.
(25) Shoenafinger, K.; Petry, S.; Mueller, G.; Barringhous, K.-H. PCT
Appl. WO 0166533, 2001.
(26) Petry, S.; Schoenafinger, K.; Mueller, G.; Barringhous, K.-H. PCT
Appl. WO 0117981, 2001.
(27) Slee, D. H.; Bhat, A. S.; Nguyen, T. N.; Kish, M.; Lundeen, K.;
Newman, M. J.; McConnell, S. J. Pyrrolopyrazinedione-based
inhibitors of hormone-sensitive lipase. J. Med. Chem. 2003, 46,
1120-1122.
(28) C. de Jong, J.; Sørensen, L. G.; Tornqvist, H.; Jacobsen, P. Carbazates
as potent inhibitors of hormone-sensitive lipase. Bioorg. Med. Chem.
Lett. 2004, 14, 1741.
(29) Ebdrup, S.; Sørebseb, L. G.; Olsen, O. H.; Jacobsen, P. Synthesis
and structure-activity relationship for a novel class of potent and
selective carbamoyl-triazole based inhibitors of hormone sensitive
lipase. J. Med. Chem. 2004, 47, 400-410.
(30) Ebdrup, S.; Jacobsen, P.; Dhanda Farrington, A.; Vedsø, P. Structure-
activity relationship for aryl and heteroaryl boronic acid inhibitors
of hormone-sensitive lipase. Bioorg. Med. Chem. 2005, 13, 2305-
2312.
(31) Wei, H.; Myers, R.; Hanney, B.; Spada, A. P.; Bilder, G.; Galzcinski,
H.; Amin, D.; Needle, S.; Page, K.; Jazzosi, Z.; Perrone, M. H. Potent
quinoxaline-based inhibitors of PDGF receptor tyrosin kinase activity.
Part 2: The synthesis and biological activities of RPR127963, an
orally bioavailable inhibitor. Bioorg. Med. Chem. Lett. 2003, 13,
3097-3100.
(32) Yeh, S. C.; Patel, J. R.; Kurukulasuriya, H. Y. R.; Fung, S.; Monzon,
K.; Chiou, W.; Wang, J.; Stolarik, D.; Imade, H.; Beno, D.; Brune,
M.; Jacobsen, P.; Sham, H.; Link, J. T. Synthesis and biological
evaluation of heterocyclic containing adamantine 11â-HSD1 inhibi-
tors. Bioorg. Med. Chem. Lett. 2006, 16, 5414-5419.
(33) Claus, T. C.; Lowe, D. B.; Liang, Y.; Salhanick, A. I.; Lubeski, C.
K.; Yang, L.; Lemoine, L.; Zhu, J.; Clairmont, A. I. Specific inhibition
of hormone-sensitive lipase improves lipid profiles with reducing
plasma glucose. J. Pharmacol. Exp. Ther. 2005, 315, 1396-1402.
(34) Contreras, J. A.; Danielsson, B.; Johansson, C.; Osterlund, T.; Langin,
D.; Holm, C. Human hormone sensitive lipasesExpression and large-
scale purification from a baculovirus/insect cell system. Protein
Expression Purif. 1998, 12, 93-99.
(35) Bengtson-Olivecrona, G.; Olivecrona, T. Phospholipase activity of
milk lipoprotein lipase. Methods Enzymol. 1991, 197, 345-356.
(36) Holm, C.; Olivecrona, G.; Ottoson, M. Assays of lipolytic enzymes.
Methods Mol. Biol. 2001, 155, 97-119.
(37) Batey, R. A.; Santhakumar, V.; Yoshina-Ishii, C.; Tayler, S. D. An
efficient new protocol for the formation of unsymmetrical tri- and
tetrasubstituted ureas. Tetrahedron Lett. 1998, 39, 6267-6270.
(38) Konakahara, T.; Ozaki, T.; Sato, K.; Gold, B. A Convenient method
for the synthesis of activated N-methylcarbamates. Synthesis 1993,
1, 103-106.
Supporting Information Available: Spectroscopic data, LC-
MS, and elemental analyses are available free of charge via the
References
(1) DeFronzo, R. A. Pathogenesis of type 2 (non-insulin dependent)
diabetes mellitus: A balanced overview. Diabetologia 1992, 35,
389-397.
(2) Unger, R. H. Lipotoxic diseases. Ann. ReV. Med. 2002, 53, 319-
336.
(3) Rossetti, L.; Giaccari, A.; DeFronzo, R. A. Glucose toxicity. Diabetes
Care 1990, 13, 610-630.
(4) McGarry, J. D. Dysregulation of fatty acid metabolism in the etiology
of type 2 diabetes. Diabetes 2002, 5, 17-18.
(5) Reaven, G. M.; Greenfield, M. S. Diabetic hypertriglyceridemia:
Evidence for three clinical syndromes. Diabetes 1981, 30, 66-75.
(6) Frayn, Κ. Ν. Adipose tissue as a buffer for daily lipid flux.
Diabetologia 2002, 45, 1201-1210.
(7) Unger, Ρ. Η. Lipotoxicity in the pathogenesis of obesity-dependent
NIDDM. Genetic and clinical implications. Diabetes 1995, 44, 863-
870.
(8) Boden, G. Role of fatty acids in the pathogenesis of insulin resistance
and NIDDM. Diabetes 1997, 46, 3-10.
(9) Boden, G.; Jadali, F.; White, J.; Liang, Y.; Mozolli, M.; Chen, X.;
Coleman, E.; Smith, C. Effects of fat on insulin stimulated carbo-
hydrate metabolism in normal men. J. Clin. InVest. 1991, 88, 960-
966.
(10) Kim, J. K.; Fillmore, J. J.; Chen, Y.; Yu, C.; Moore, I. K.; Pypaert,
M.; Lutz, E. P.; Kako, Y.; Velez-Carrasco, W.; Goldberg, I. J.;
Breslow, J.; Schulman, G. I. Tissue-specific overexpression of
lipoprotein lipase causes tissue-specific insulin resistance. Proc. Natl.
Acad. Sci. U.S.A. 2001, 98, 7522-7527.
(11) Ferranini, E.; Barret, E. J.; Bevilacqua, S.; DeFronzo, R. A. Effect
of fatty acids on glucose production and utilization in man. J. Clin.
InVest. 1983, 72, 1737-1747.
(12) Boden, G.; Jadali, F. Effects of lipid on basal carbohydrate
metabolism in normal men. Diabetes 1991, 40, 686-692.
(13) Large, V.; Arner, P. Regulation of lipolysis in humans. Pathophysi-
ological modulation in obesity, diabetes and hyperlipidemia. Diabetes
Metab. 1998, 24, 409-418.
(14) Groop, L. C.; Saloranta, C.; Shank, M.; Bonadonna, R. C.; Ferrannni,
E.; DeFronzo, R. A. The role of free fatty acid metabolism in the
pathogenesis of insulin resistance in obesity and noninsulin-dependent
diabetes mellitus. J. Clin. Endocrinol. Metab. 1991, 72, 96-107.
(15) Ginsberg, H.; Plutzky, J.; Sobel, E. Review of metabolic and
cardiovascular effects of oral antidiabetic agents: Beyond glucose-
level lowering. J. CardioVasc. Risk 1999, 6, 337-346.
(16) Miles, J. M.; Wooldridge, D.; Grellner, W. J.; Windsor, S.; Isley,
W. L.; Kelin, S.; Harris, W. S. Nocturnal and postprandial free fatty
acid kinetics in normal and type 2 diabetic subjects. Diabetes 2003,
52, 675-681.
(17) Coppack, S. W.; Evans, R. D.; Fischer, R. M.; Frayn, K. N.; Gibbons,
G. F.; Humphreys, S. M.; Kirk, M. L.; Potts, J. L.; Hockaday, T. D.
Adipose tissue metabolism in obesity: Lipase action in vivo before
and after a mixed meal. Metabolism 1992, 41, 264-272.
(18) Kraemer, F. B.; Shen, W.-J. Hormone sensitive lipase: Control of
intracellular tri-(di)-acylglycerol and cholesteryl ester hydrolyses. J.
Lipid. Res. 2002, 43, 1585-1594.
(19) Langin, D.; Holm, C.; LaFontan, M. Adipocyte hormone sensitive
lipase: a major regulator of lipid metabolism. Proc. Nutr. Soc. 1996,
55, 93-109.
(39) Watson, K. G.; Serban, A. Evaluation of the elbs persulfate oxidation
reaction for the preparation of aryloxyphenoxypropionate herbicides.
Aust. J. Chem. 1995, 48, 8, 1503-1510.
JM0607653