4362
S. Olson et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4359–4362
Table 3. SAR of n-alkyl-substituted adamantyl triazoles
Compound
R1
R2
IC50 (nM)
Mouse pharmacodynamic
assay (% inhibition)
Human
11b-HSD1
Mouse
11b-HSD1
Human
11b-HSD2
Mouse
11b-HSD2
1 h
4 h
18
19
20
21
22
23
Methyl
Ethyl
Butyl
Propyl
Ethyl
11
52
11
72
3
91
50
2840
<4000
>4000
>4000
92
>4000
>4000
50
31
24
55
—
48
85
21
5
Propyl
Butyl
23
37
—
23
47
Methyl
Benzyl
Phenyl
270
14
>4000
>4000
>4000
Methyl
Methyl
37
109
>4000
˚
8. (a) Barf, T.; Vallgarda, J.; Emond, R.; Ha¨ggstro¨m, C.;
Kurz, G.; Nygren, A.; Larwood, V.; Mosialou, E.;
Axelsson, K.; Olsson, R.; Engblom, L.; Edling, N.;
Replacing the alkyl substituents on the eastern half of
the molecule with a phenyl group, as in 23, enhances
pharmacodynamic activity without changing the overall
polarity of the inhibitor. Additional optimization of
these lead compounds may eventually lead to a treat-
ment strategy for metabolic syndrome.
¨
´
Ro¨nquist-Nii, Y.; Ohman, B.; Alberts, P.; Abrahmsen,
L. J. Med. Chem. 2002, 45, 3813; (b) Fotsch, C.; Askew, B.
C.; Chen, J. J. Expert Opin. Ther. Patents 2005, 15, 289;
(c) Schweizer, R. A. S.; Atanasov, A. G.; Frey, B. M.;
Odermatt, A. Mol. Cell. Endocrinol. 2003, 212, 41; (d)
Diederich, S.; Grossmann, C.; Hanke, B.; Quinkler, M.;
Herrmann, M.; Bahr, V.; Oelkers, W. Eur. J. Endocrinol.
2000, 142, 200; (e) Koch, M. A.; Wittenberg, L.-O.; Basu,
S.; Jeyaraj, D. A.; Gourzoulidou, E.; Reinecke, K.;
Odermatt, A.; Waldmann, H. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 16721; (f) Xiang, J.; Ipek, M.; Suri, V.;
Massefski, W.; Pan, N.; Ge, Y.; Tam, M.; Xing, Y.; Tobin,
J. F.; Tam, S. Bioorg. Med. Chem. Lett. 2005, 15, 2865.
9. The in vitro enzymatic activity was assessed via a
scintillation proximity assay (SPA). Tritiated-cortisone,
NADPH, and test compound were incubated with 11b-
HSD1 from CHO transfectants at 37 °C to allow conver-
sion to cortisol to progress. Following incubation, a
preparation of protein A-coated SPA beads, pre-blended
with anti-cortisol monoclonal antibody MAb and a
nonspecific 11b-HSD1 inhibitor (18b-glycyrrhetinic acid),
was added to each well. The mixture was read on a
scintillation counter. This is similar to the method
described in Ref. 8a.
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