B. Sorensen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 527–532
Table 3. Pharmacokinetic results for sulfonamides 40 and 18 and sulfone 10
531
a
a
a
a
a
a
Compound
Species
Dose (mpk)
iv t1/2 (h)
V
ss (L/kg)
V
b
L/kg
iv CLp (L/h/kg)
po AUC (lg h/mL)
F (%)
40
18
10
10
Mouse
Mouse
Mouse
Monkey
10
5 iv, 10 oral
2.8
1.8
1.0
5.1
2.6
2.1
1.5
2.7
3.5
2.1
1.7
3.1
0.9
0.8
1.1
0.4
7.0
18.3
8.9
61
150
100
109
10
2.5
6.81
a
Values are means obtained from samples taken from three animals.
Table 4. Metabolic stability results for compound 10
Acknowledgments
a
Intrinsic clearance (L/h/kg)
Species
Liver microsomes
Hepatocyte
Rob Gregg is acknowledged for suggesting methods for
the preparation of adamantane sulfonamides. Larry
Solomon, Karl Walter, and Diane Bartlet are thanked
for the cloning and expression of the h-HSD1 construct
used in the crystallography experiments. Steve Cepa and
Dr. Lan Gao are thanked for determination of the cor-
tisol levels in ex vivo samples. Robin Shapiro, Victoria
Knourek-Segal, Tom Fey, Brian Droz, and Kelly Lar-
son are acknowledged for their assistance with the ex vi-
vo experiments. David Beno and Frank Kerdesky are
thanked for the design of pharmacokinetic experiments
and providing multigram quantities of an early interme-
diate, respectively.
Mouse
Monkey
Human
6.0
1.5
1.6
0.2
0.1
ND
a
Values are means of three experiments (ND, not determined).
Table 5. Ex vivo study in DIO mice for compounds 10 and 40
a
Compound
% inhibition
Liver (1, 7, 16 h) Fat (1, 7, 16 h) Brain (1, 7, 16 h)
1
4
0
0
95, 95, 89
70, 78, 82
87, 93, 86
62, 88, 93
90, 90, 77
29, 48, 73
a
Values are means from samples taken from two animals.
References and notes
assessed in mouse and monkey microsomes and hepato-
cytes (Table 4). The compound shows greater stability in
monkey microsomes relative to mouse, which is similar
to the trend observed with other adamantanes. Human
liver microsomes give a similar metabolic stability to
monkey, and little difference was noted in hepatocytes.
1
. (a) Fotsch, C.; Askew, B. C.; Chen, J. J. Expert Opin.
Ther. Patents 2005, 15, 289; (b) Barf, T.; Williams, M.
Drugs Future 2006, 31, 231.
8
2. Walker, B. R.; Seckl, J. R. Expert Opin. Ther. Targets
003, 7, 771.
. (a) Masuzaki, H.; Paterson, J.; Shinyama, H. Science
001, 294, 2166; (b) Masuzaki, H.; Yamamoto, H.;
2
3
2
Kenyon, C. J.; Elmquist, J. K.; Morton, N. M.; Paterson,
J. M.; Shinyama, H.; Sharp, M. G. F.; Fleming, S.;
Mullins, J. J.; Seckl, J. R.; Flier, J. S. J. Clin. Invest. 2003,
To determine the capacity of these compounds to inhibit
liver, fat, and brain 11-b-HSD1, the compounds were
orally dosed at 30 mpk in DIO mice (Table 5). At sever-
al timepoints thereafter (1, 7, and 16 h), the animals
were sacrificed, and the ex vivo tissue inhibition assessed
relative to vehicle. Sulfone 10 robustly inhibited liver,
fat, and brain 11-b-HSD1 up to 16 h post-dose, indicat-
ing long and potent coverage in these tissues. Sulfon-
amide 40 also shows potent and long duration
inhibition in liver and fat, although its brain inhibition
is initially modest and builds over time. This suggests
it may be a good lead to modify to discover inhibitors
that work in liver and fat, but fail to penetrate the cen-
tral nervous system. Such a compound may potentially
have greater efficacy and/or fewer side effects due to re-
duced HPA axis activation.
1
12, 83.
4
. (a) Kotelevtsev, Y.; Holmes, M. C.; Burchell, A.; Hous-
ton, P. M.; Schmoll, D.; Jamieson, P.; Best, R.; Brown, R.;
Edwards, C. R. W.; Seckl, J. R.; Mullins, J. J. Proc. Natl.
Acad. Sci. U.S.A. 1997, 94, 14924; (b) 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. Diabetes 2004, 53, 931; (c) Morton, N. M.; Holmes,
M. C.; Fi e´ vet, C.; Staels, B.; Tailleux, A.; Mullins, J. J.;
Seckl, J. R. J. Biol. Chem. 2001, 276, 41293; (d) Yau, J. L.
W.; Noble, J.; Kenyon, C. J.; Hibberd, C.; Kotelevtsev,
Y.; Mullins, J. J.; Seckl, J. R. Proc. Natl. Acad. Sci. 2001,
9
8, 4716.
5. Sandeep, T. C.; Yau, J. L. W.; MacLullich, A. M. J.;
Noble, J.; Deary, I. J.; Walker, B. R.; Seckl, J. R. Proc.
Natl. Acad. Sci. 2004, 101, 6734.
6
. (a) Barf, T.; Vallg a˚ rda, J.; Emond, R.; H a¨ ggstr o¨ m,
C.; Kurz, G.; Nygren, A.; Larwood, V.; Mosialou,
E.; Axelsson, K.; Olsson, R.; Engblom, L.; Edling,
Novel adamantane sulfone and sulfonamides were dis-
covered that potently and selectively inhibit both human
and mouse 11-b-HSD1. Representative members of
these two series have mouse pharmacokinetic profiles
that make them interesting tool compounds to assess
the effects of 11-b-HSD1 inhibition. In particular,
sulfone 10 provides potent inhibition in liver, fat, and
brain HSD1 up to 16 h post-dose in DIO mice, while
sulfonamide 40 gives similar activity with less brain
inhibition.
¨
N.; R o¨ nquist-Nil, Y.; Ohman, B.; Alberts, P.; Abra-
hms e´ n, L. J. Med. Chem. 2002, 45, 3813; (b)
Alberts, P.; Engblom, L.; Edling, N.; Forsgren, M.;
¨
Klingstr o¨ m, G.; Larsson, C.; R o¨ nquist-Nii, Y.; Oh-
man, B.; Abrahms e` n, L. Diabetologia 2002, 45, 1528;
(c) Alberts, P.; Nilsson, C.; Sel e´ n, G.; Engblom, L.
O. M.; Edling, N. H. M.; Norling, S.; Klingstr o¨ m,
G.; Larsson, C.; Forsgren, M.; Ashkzari, M.; Nils-