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M. Maletic et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2568–2572
Table 75
O O
S
F3C
N
N N
22
Speciesa
Dose IV/PO (mg/kg)
PO AUCN (
lM h kg/mg)
Cl (mL/min/kg)
Vd (L/kg)
t1/2 (h)
CmaxN (lM kg/mg)
Tmax (h)
F (%)
Mouse
Rat
Dog
2/10
1/4
0.5/2
0.5/2
4.6
13.0
14.2
8.3
2.1
2.9
1.9
4.0
0.72
1.1
1.7
4.8
4.9
12.2
6.5
0.47
1.22
1.06
1.35
5
2
2
2
24
87
59
89
Rhesus
1.6
a
PK was determined in male C57 mice, male Sprague–Dawley rats, and Beagle dogs.
S. t.; Wang, M.; Fotsch, C. Curr. Top. Med. Chem. 2008, 8, 1508; (d) Boyle, C. D.
Curr. Opin. Drug Discov. Devel. 2008, 11, 495; (e) Boyle, C. D.; Kowalski, T. J. Exp.
Opin. Ther. Pat. 2009, 19, 801; (f) Singh, S. B.; Tice, C. M. Curr. Pharm. Biotechnol.
2010, 11, 779.
efficacy. Finally, several other ortho-substituted analogs were also
prepared (38–40), but did not provide an advantage with respect
to in vitro or in vivo potency over analog 22.
3. Waddell, S. T.; Balkovec, J. M.; Graham, D.; Patel, G.; Dragovic, J.; LeGrand, C.;
Mundt, S. S.; Shah, K.; Springer, M. S.; Tan, E. Y.; Thieringer, R.; Hermanovski-
Vosatka, A.; Zokian, H. J. Bioorg. Med. Chem. Lett., submitted for publication.
4. For a detailed summary of the in vitro and in vivo assays see: Hermanovski-
Vosatka, A.; Balkovec, J.; 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. J.; Xiao, J.; Zhang, B. B.; Wright, S.
D.; Thieringer, R. J. Exp. Med. 2005, 202, 517.
5. PK parameters were based on whole blood drug levels for mouse and plasma
for all other species. All the compounds were dosed as a solution in 5–30%
hydroxypropyl b-cyclodextrin vehicle.
6. Gu, X.; LeGrand, C.; Dragovic, J.; Shah, K.; Mundt, S. S.; Koo, G. C.; Zokian, H. J.;
Thieringer, R.; Hermanowski-Vosatka, A.; Springer, M.; Balkovec, J. M.;
Waddell, S. T. Bioorg. Med. Chem. Lett. 2005, 15, 5266.
7. Koldobskii, G.; Ivanova, S.; Nikonova, I.; Zhivich, A. R.; Ostrovskii Acta Chem.
Scand. 1994, 48, 596.
8. Zhu, Y.; Olson, S. H.; Hermanowski-Vosatka, A.; Mundt, S. S.; Shah, K.; Xiao, J.;
Gao, Y.; Springer, M. S.; Thieringer, R.; Wright, S. D.; Zokian, H. J.; Balkovec, J. M.
Bioorg. Med. Chem. Lett. 2008, 18, 3405.
9. Gao, Y.-D.; Olson, S. H.; Balkovec, J. M.; Zhu, Y.; Royo, I.; Ismail, J.; Hartley, D.;
Mosley, R. Xenobiotica 2007, 37, 124.
10. Waddell, S. T.; Santorelli, G. M.; Maletic, M. M.; Leeman, A. H.; Gu, X.; Graham,
D. W.; Balkovec, J. M.; Aster, S. D. PCT Int. Appl., WO 2004106294 A2, 2004, pp
46.
11. While mouse PK was not obtained on all the compounds described in this
communication, plasma levels of compound were determined in mice
following the PD studies. There was generally a good correlation between
efficacy and compound levels in plasma for the compounds in Tables 4 and 5;
compounds with decreased plasma exposures showed lowered efficacy in
extended PD.
12. Unpublished results; (a) Maletic, M.; Leeman, A.; Mundt, S.; Zokian, H.; Shah,
K.; Dragovic, J.; Lyons, K.; Tan, E.; Thieringer, R.; Vosatka, A.; Springer, M.;
Balkovec, J.; Waddell, S. T. ‘Bicyclo[2.2.2]octyltriazole inhibitors of 11b-HSD type
1: Pharmacological agents for the treatment of metabolic syndrome’ Metabolic
Syndrome and Cardiovascular Risk Keystone Symposium, Steamboat Springs,
CO, Mar 28–Apr 1, 2007; Poster 224; (b) Maletic, M.; Leeman, A.; Waddell, S. T.;
Balkovec, J. ‘Bicyclo[2.2.2]octyltriazole inhibitors of 11b-HSD type 1:
Pharmacological agents for the treatment of metabolic syndrome’ 231st ACS
National Meeting, Atlanta, GA, Mar 26–30, 2006; MEDI-196.
Based on these SAR studies, we determined that the optimized
sulfone analog 22 had superior in vitro and in vivo HSD1 potency.
The compound also had a desirable physical property profile,
exhibiting water solubility of >1 mg/ml and a relatively low HPLC
log D of 2.2. Evaluation of pharmacokinetic properties of this com-
pound in four species indicated an excellent profile with a slow
rate of clearance, moderate half-life and good bioavailability across
species (Table 7) Additionally, compound 22 was evaluated in hu-
man liver microsomes for Cyp induction potential and was shown
not to be an inducer (with human PXR activation at 10 lM <10%).
The compound was further tested in several rodent models of met-
abolic disease. It showed efficacies in the Diet Induced Obesity
mouse model (DIO), apo-E knockout mouse model of atherosclero-
sis and Oral Glucose Tolerance Test (OGTT) in B6-Ay mouse.
Detailed efficacy studies on this compound are still in progress
and will be published elsewhere.12
In summary, we described the synthesis and SAR studies of a set
of alkyl substituted [2.2.2]bicyclooctane triazole inhibitors of
HSD1. We showed the progression from an active pentyl chain
analog 3 with poor physical and pharmacokinetic properties to a
highly selective and efficacious sulfone analog 22. With this com-
pound we showed a significant improvement in the pharmacoki-
netic profile over the initial lead. Finally, we used this compound
to demonstrate efficacy in three different rodent metabolic disease
models. Further studies of compound 22 and analogs are ongoing
and will be subject of additional reports from our laboratories.
References and notes
1. (a) Alberti, K. G. M. M.; Zimmet, P.; Shaw, J. Diabet. Med. 2006, 23, 469; (b)
Stern, M.; Williams, K.; Gonzalez-Villalpando, C., et al Diabetes Care 2004, 27,
2676; Beilby, J. Clin. Biochem. Rev. 2004, 25, 195.
2. (a) Hughes, K. A.; Webster, S. P.; Walker, B. R. Expert Opin. Investig. Drugs 2008,
17, 481; (b) Hale, C.; Wang, M. Mini-Rev. Med. Chem. 2008, 8, 702; (c) Jean, D. J.