Letters
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 3 431
(4) Wang, M. The role of glucocorticoid action in the pathophysiology
of the metabolic syndrome. Nutr. Metab. (London) 2005, 2, 3.
(5) Kannisto, K.; Pietilaeinen, K. H.; Ehrenborg, E.; Rissanen, A.; Kaprio,
J.; Hamsten, A.; Yki-Jaervinen, H. Overexpression of 11â-hydrox-
ysteroid dehydrogenase-1 in adipose tissue is associated with acquired
obesity and features of insulin resistance: Studies in young adult
monozygotic twins. J. Clin. Endocrinol. Metab. 2004, 89, 4414-
4421.
(6) Rask, E.; Olsson, T.; Soderberg, S.; Andrew, R.; Livingstone, D. E.
W.; Johnson, O.; Walker, B. R. Tissue-specific dysregulation of
cortisol metabolism in human obesity. J. Clin. Endocrinol. Metab.
2001, 86, 1418-1421.
(7) Masuzaki, H.; Paterson, J.; Shinyama, H.; Morton, N. M.; Mullins,
J. J.; Seckl, J. R.; Flier, J. S. A transgenic model of visceral obesity
and the metabolic syndrome. Science 2001, 294, 2166-2170.
(8) Kotelevitsev, Y.; Holmes, M. C.; Burchell, A.; Houston, P. M.;
Schmoll, D.; Jamieson, P.; Best, R.; Brown, R.; Edwards, C. R. W.;
Seckl, J. R.; Mullins, J. J. 11â-Hydroxysteroid dehydrogenase type
1 knockout mice show attenuated glucocorticoid-inducible responses
and resist hyperglycemia on obesity or stress. Proc. Natl. Acad. Sci.
U.S.A. 1997, 94, 14924-14929.
(9) Morton, N. M.; Paterson, J. M.; Masuzaki, H.; Holmes, M. C.; Staels,
B.; Fievet, C.; Walker, B. R.; Flier, J. S.; Mullins, J. J.; Seckl, J. R.
Novel adipose tissue-mediated resistance to diet-induced visceral
obesity in 11â-hydroxysteroid dehydrogenase type 1-deficient mice.
Diabetes 2004, 53, 931-938.
(10) Kershaw, E. E.; Morton, N. M.; Dhillon, H.; Ramage, L.; Seckl, J.
R.; Flier, J. S. Adipocyte-specific glucocorticoid inactivation protects
against diet-induced obesity. Diabetes 2005, 54, 1023-1031.
(11) Alberts, P.; Nilsson, C.; Selen, G.; Engblom, L. O. M.; Edling, N.
H. M.; Norling, S.; Klingstroem, G.; Larsson, C.; Forsgren, M.;
Ashkzari, M.; Nilsson, C. E.; Fiedler, M.; Bergqvist, E.; Oehman,
B.; Bjoerkstrand, E.; Abrahmsen, L. B. Selective inhibition of 11â-
hydroxysteroid dehydrogenase type 1 improves hepatic insulin
sensitivity in hyperglycemic mice strains. Endocrinology 2003, 144,
4755-4762.
(12) Hermanowski-Vosatka, A.; Balkovec, J. M.; Cheng, K.; Chen, H.
Y.; Hernandez, M.; Koo, G. C.; Le Grand, C. B.; Li, Z.; Metzger, J.
M.; Mundt, S. S.; Noonan, H.; Nunes, C. N.; Olson, S. H.; Pikounis,
B.; Ren, N.; Robertson, N.; Schaeffer, J. M.; Shah, K.; Springer, M.
S.; Strack, A. M.; Strowski, M.; Wu, K.; Wu, T.; Xiao, J.; Zhang,
B. B.; Wright, S. D.; Thieringer, R. 11â-HSD1 inhibition ameliorates
metabolic syndrome and prevents progression of atherosclerosis in
mice. J. Exp. Med. 2005, 202, 517-527.
(13) Barf, T.; Vallgrda, J.; Emond, R.; Haeggstroem, C.; Kurz, G.; Nygren,
A.; Larwood, V.; Mosialou, E.; Axelsson, K.; Olsson, R.; Engblom,
L.; Edling, N.; Roenquist-Nii, Y.; Oehman, B.; Alberts, P.; Abrahm-
sen, L. Arylsulfonamidothiazoles as a new class of potential
antidiabetic drugs. Discovery of potent and selective inhibitors of
the 11â-hydroxysteroid dehydrogenase type 1. J. Med. Chem. 2002,
45, 3813-3815.
(14) Coppola, G. M.; Kukkola, P. J.; Stanton, J. L.; Neubert, A. D.;
Marcopulos, N.; Bilci, N. A.; Wang, H.; Tomaselli, H. C.; Tan, J.;
Aicher, T. D.; Knorr, D. C.; Jeng, A. Y.; Dardik, B.; Chatelain, R.
E. Perhydroquinolylbenzamides as novel inhibitors of 11â-hydrox-
ysteroid dehydrogenase type 1. J. Med. Chem. 2005, 48, 6696-6712.
(15) Gu, X.; Dragovic, J.; Koo Gloria, C.; Koprak Sam, L.; LeGrand, C.;
Mundt, S. S.; Shah, K.; Springer, M. S.; Tan, E. Y.; Thieringer, R.;
Hermanowski-Vosatka, A.; Zokian Hratch, J.; Balkovec, J. M.;
Waddell, S. T. Discovery of 4-heteroarylbicyclo[2.2.2]octyltriazoles
as potent and selective inhibitors of 11â-HSD1: Novel therapeutic
agents for the treatment of metabolic syndrome. Bioorg. Med. Chem.
Lett. 2005, 15, 5266-5269.
(16) Olson, S.; Aster, S. D.; Brown, K.; Carbin, L.; Graham, D. W.;
Hermanowski-Vosatka, A.; LeGrand, C. B.; Mundt, S. S.; Robbins,
M. A.; Schaeffer, J. M.; Slossberg, L. H.; Szymonifka, M. J.;
Thieringer, R.; Wright, S. D.; Balkovec, J. M. Adamantyl triazoles
as selective inhibitors of 11â-hydroxysteroid dehydrogenase type 1.
Bioorg. Med. Chem. Lett. 2005, 15, 4359-4362.
(17) Xiang, J.; Ipek, M.; Suri, V.; Massefski, W.; Pan, N.; Ge, Y.; Tam,
M.; Xing, Y.; Tobin, J. F.; Xu, X.; Tam, S. Synthesis and biological
evaluation of sulfonamidooxazoles and â-keto sulfones: Selective
inhibitors of 11â-hydroxysteroid dehydrogenase type I. Bioorg. Med.
Chem. Lett. 2005, 15, 2865-2869.
(18) Schuster, D.; Maurer, E. M.; Laggner, C.; Nashev, L. G.; Wilckens,
T.; Langer, T.; Odermatt, A. The discovery of new 11â-hydroxy-
steroid dehydrogenase type 1 inhibitors by common feature phar-
macophore modeling and virtual screening. J. Med. Chem. 2006, 49,
3454-3466.
Figure 2. Acute effects of thiazolone 17 as assessed by ex vivo
cortisone to cortisol turnover. Percent inhibition of adipose tissue
enzyme activity (solid bars) is compared to adipose (solid squares) and
plasma (open circles) concentration levels of 17. Adipose and plasma
drug levels are expressed as mean ( SEM of n ) 3.
assayed for 11â-HSD1 activity. As shown in Figure 2, adipose
11â-HSD1 enzymatic activity was substantially reduced. Rela-
tive to vehicle controls, 11â-HSD1 activity in animals treated
with 17 was reduced by 88% 2 h after dosing and remained
reduced by 91% 6 h post-dose. Absolute levels of 17 were
measured in plasma and adipose of these same animals. Levels
in adipose ranged from 234 µM at 2 h to 113 µM at 6 h, while
plasma levels were 55 µM at 2 h to 35 µM at 6 h.
In summary, through modifications of our original lead 1,
we discovered the potent 11â-HSD1 inhibitor 11 (SPA Ki and
whole cell IC50 ) 4 nM). Although potent, thiazolone 11
displayed high in vivo clearance in rats. By replacing the
metabolically labile isopropyl moiety at C-5, we were able to
overcome this liability. Trifluoromethyl derivative 17 not only
possessed a desirable rat PK profile but also exhibited good
potency (SPA Ki ) 22 nM). Furthermore, we have demonstrated
that thiazolone 17 can substantially inhibit adipose 11â-HSD1
enzymatic activity in a mouse ex vivo PD model.
Acknowledgment. We thank Dr. Rashid Syed and Dr.
Richard J. Staples for determining the X-ray structures of 11
and 17.
Supporting Information Available: Experimental details for
the synthesis and characterization of all compounds as well as the
X-ray crystal data for 11 and 17. This material is available free of
References
(1) Arnaldi, G.; Angeli, A.; Atkinson, A. B.; Bertagna, X.; Cavagnini,
F.; Chrousos, G. P.; Fava, G. A.; Findling, J. W.; Gaillard, R. C.;
Grossman, A. B.; Kola, B.; Lacroix, A.; Mancini, T.; Mantero, F.;
Newell-price, J.; Nieman, L. K.; Sonino, N.; Vance, M. L.; Giustina,
A.; Boscaro, M. Diagnosis and complications of Cushing’s syn-
drome: A consensus statement. J. Clin. Endocrinol. Metab. 2003,
88, 5593-5602.
(2) Grundy, S. M.; Brewer, H. B., Jr.; Cleeman, J. I.; Smith, S. C., Jr.;
Lenfant, C. Definition of metabolic syndrome: Report of the National
Heart, Lung, and Blood Institute/American Heart Association confer-
ence on scientific issues related to definition. Circulation 2004, 109,
433-438.
(3) Faggiano, A.; Pivonello, R.; Spiezia, S.; De Martino, M. C.; Filippella,
M.; Di Somma, C.; Lombardi, G.; Colao, A. Cardiovascular risk
factors and common carotid artery caliber and stiffness in patients
with cushing’s disease during active disease and 1 year after disease
remission. J. Clin. Endocrinol. Metab. 2003, 88, 2527-2533.
(19) Su, X.; Vicker, N.; Ganeshapillai, D.; Smith, A.; Purohit, A.; Reed,
M. J.; Potter, B. V. L. Benzothiazole derivatives as novel inhibitors
of human 11â-hydroxysteroid dehydrogenase type 1. Mol. Cell.
Endocrinol. 2006, 248, 214-217.