Spirocyclic ureas: Orally bioavailable 11β-HSD1 inhibitors identified by computer-aided drug design

Article abstract of DOI:10.1016/j.bmcl.2009.12.082

Structure-guided drug design led to the identification of a class of spirocyclic ureas which potently inhibit human 11β-HSD1 in vitro. Lead compound 10j was shown to be orally bioavailable in three species, distributed into adipose tissue in the mouse, and its (R) isomer 10j2 was efficacious in a primate pharmacodynamic model.

Full text of DOI:10.1016/j.bmcl.2009.12.082

Bioorganic & Medicinal Chemistry Letters 20 (2010) 881–886
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Spirocyclic ureas: Orally bioavailable 11b-HSD1 inhibitors identified
by computer-aided drug design
*
Colin M. Tice , Wei Zhao, Zhenrong Xu, Salvacion T. Cacatian, Robert D. Simpson, Yuan-Jie Ye,
Suresh B. Singh, Brian M. McKeever, Peter Lindblom, Joan Guo, Paula M. Krosky, Barbara A. Kruk,
Jennifer Berbaum, Richard K. Harrison, Judith J. Johnson, Yuri Bukhtiyarov, Reshma Panemangalore,
Boyd B. Scott, Yi Zhao, Joseph G. Bruno, Linghang Zhuang, Gerard M. McGeehan, Wei He, David A. Claremon
Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Structure-guided drug design led to the identification of a class of spirocyclic ureas which potently inhibit
human 11b-HSD1 in vitro. Lead compound 10j was shown to be orally bioavailable in three species, dis-
tributed into adipose tissue in the mouse, and its (R) isomer 10j2 was efficacious in a primate pharma-
codynamic model.
Received 11 November 2009
Revised 17 December 2009
Accepted 18 December 2009
Available online 4 January 2010
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Spirocycles
11b-Hydroxysteroid dehydrogenase
Structure-based drug design
Diabetes
11b-hydroxysteroid dehydrogenase (11b-HSD1) is a member of
the short chain dehydrogenase/reductase (SDR) superfamily. 11b-
HSD1 increases local tissue concentrations of the active glucocorti-
coid cortisol by NADPH-dependent reduction of inactive cortisone.
It is primarily expressed in liver and adipose tissue, and its ele-
vated expression in adipose tissue has been linked to obesity, insu-
lin resistance, diabetes and cardiovascular disease1–5 in humans.
Moreover, the phenotype of transgenic mice overexpressing 11b-
HSD1 in adipose tissue includes visceral obesity, insulin resistance
and hypertension,6,7 while 11b-HSD1 knockout mice are resistant
to diet induced obesity and have increased insulin sensitivity.8–10
Thus, a selective inhibitor of 11b-HSD1 may be useful for the treat-
ment of diabetes and has the potential for positive effects on multi-
ple cardiovascular risk parameters.
dosing of thiazolone 3 has been reported to increase plasma adipo-
c
nectin levels and decrease fasting glucose levels in KKA mice.18,19
Carbenoxolone (1, Fig. 1), a semisynthetic derivative of the nat-
ural product 18b-glycyrrhetinic acid, is a nonselective inhibitor of
11b-HSD1 and of 11b-HSD2, which catalyzes the NAD-dependent
oxidation of cortisol to cortisone. Despite its lack of selectivity
for 11b-HSD1, 1 has been investigated in animal and human stud-
ies where it improved insulin sensitivity.11,12 Since 2002,13 more
selective, synthetic inhibitors of 11b-HSD1 have been re-
ported.14–16 Triazole 2 increased insulin sensitivity and decreased
fasting glucose, cholesterol, and adipose tissue mass in mice.17 Oral
* Corresponding author. Tel.: +1 215 461 2042; fax: +1 215 461 2006.
E-mail address: ctice@vitaerx.com (C.M. Tice).
Figure 1. Literature 11b-HSD1 inhibitors.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.12.082

882
C. M. Tice et al. / Bioorg. Med. Chem. Lett. 20 (2010) 881–886
Figure 2. Protein ligand hydrogen bonding interactions. (a) Carbenoxolone 1 based on 2bel, (b) N-(2-adamantyl)amide 5 based on 2irw.
Animal studies have been reported on a number of sulfonamide
inhibitors.20–22 For example, piperazine sulfonamide 4 reduced
fed glucose and fasted insulin in mice when incoporated into a
high fat diet at 30 mg/kg/day.22 The activity of these compounds
in animal models further validates the potential for selective inhib-
itors of 11b-HSD1 in the treatment of diabetes.
11b-HSD1 (PDB code: 2irw) was published and confirmed the
validity of our model.25
The model also predicted that ureas of 2-aminoadamantane
would also be well accommodated within the binding site. Thus
simple urea 6a was prepared and had an enzyme IC50 of 16.1 nM
(Table 1). Based on these observations, we initiated a medicinal
chemistry program to improve potency, selectivity and physical
properties of urea 6a, enabled by additional modeling.
Ureas of general structures 6 and 10 were prepared from 2-ami-
noadamantane and commercially available piperidines 7 and spi-
ropiperidine esters 8 (Scheme 1).35 2-Aminoadamantane was
activated for urea formation as its isocyanate, its p-nitrophenylcar-
bamate or its (1-imidazolyl) carbonyl derivative. Hydrolysis of es-
ters 9a–j with LiOH gave carboxylic acid analogs 10a–j. The esters
of 9b and 9j were separated by chromatography on a chiral column
and hydrolyzed to give the single enantiomers of 10b and 10j.
Acylsulfonamide 10k and carboxamide 10l were prepared by
EDC catalyzed reaction of acid 10j with methanesulfonamide and
ammonia, respectively. Alcohol 10m was prepared by LiAlH4
reduction of 10j. The configuration of 10j2, the more potent enan-
tiomer of 10j, was determined to be (R) based on X-ray crystallog-
raphy of sulfonamide derivative 11 (Scheme 2).
Prior to initiation of our medicinal chemistry program, we
examined the publicly available crystal structures of 11b-HSD1,
focusing on 2bel in which carbenoxolone (1) is bound to the hu-
man form of the enzyme.23 The triad of residues Ser170, Tyr183
and Lys187 are characteristic of the SDR superfamily and are in-
volved in the catalytic cycle of the enzyme. The side chain hydroxyl
of Tyr183 donates a hydrogen bond to the E-ring carboxylate of
ligand 1, while the side chain hydroxyl of Ser170 and the backbone
NH of Ala172 donate hydrogen bonds to the ketone oxygen of 1
(Fig. 2a). Further inspection revealed that the enzyme has large,
primarily hydrophobic pockets on both sides of the catalytic triad.
One of these (Pocket I) is formed by the NAD cofactor, Thr124,
Leu126 and Val180. The second hydrophobic pocket (Pocket II) is
formed by Leu126, Val180 and Tyr177. Because the B chain of
the protein is truncated in 2bel, Pocket II appears to have a large
opening to solvent; however, the physiologically active form of
11b-HSD1 is dimeric24 and subsequent protein structures with
longer B chain constructs have revealed a smaller opening to sol-
vent formed by Asp217, Tyr280 and Tyr177.25–30 In fact, residues
from the C-terminus of the ‘B’ monomer form part of the ligand
binding pocket of the ‘A’ monomer and vice versa.
Compounds were assayed for inhibition of 11b-HSD1 in en-
zyme- and cell-based assays. Both measured the conversion of
[3H]-cortisone to [3H]-cortisol, which was quantified using SPA
Table 1
Consistent with the presence of two spacious hydrophobic
pockets, a number of adamantane containing 11b-HSD1 inhibitors
have been reported in the literature.31–34 Using ContourTM, a pro-
prietary structure-based drug design program, models of a number
of known ligands incorporating an N-(2-adamantyl)amide moiety
were generated within the binding site of 11b-HSD1. The most sat-
isfactory poses were obtained with the adamantane ring system
positioned in hydrophobic Pocket I and the carbonyl oxygen posi-
tioned between Ser170 and Tyr183 such that it accepted hydrogen
bonds from the side chain hydroxyl groups of both amino acids
(Fig. 2b). The amide NH, however, did not participate in a hydrogen
bonding interaction. Subsequent to these designs, an X-ray struc-
SAR of adamantyl piperidine ureas 6
R1
R2
H
N
N
O
Compd No.
R1
R2
Enzyme IC50 (nM)
6a
6b
6c
6d
6e
6f
H
H
H
H
H
H
H
H
16.1
1.4
0.9
1.1
2.2
0.8
0.9
2-Bn
3-Bn
4-Bn
2-Ph
3-Ph
4-Ph
ture of N-(2-adamantyl)amide
5 ( Fig. 3) bound to human
6g
6h
6i
3
0.7
0.8
4
6j
6k
4-Ph
4-Ph
4-CONH2
4-OH
41.6
56.8
Figure 3. Adamantyl amide and urea inhibitors.

C. M. Tice et al. / Bioorg. Med. Chem. Lett. 20 (2010) 881–886
883
Scheme 1. Synthesis of inhibitors 6 and 10. R1, R2, X and n are as defined in Tables 1 and 2. Reagents and conditions: (a) 2-adamantyl isocyanate, i-Pr2NEt, CH2Cl2 or p-
nitrophenyl (2-adamantyl)carbamate, i-Pr2NEt, CH2Cl2 or 2-aminoadamantane, carbonyl diimidazole, CH2Cl2; (b) LiOH, H2O, MeOH; (c) MeSO2NH2, EDC, DMAP, CH2Cl2; (d)
NH3, EDC, HOBt, i-Pr2NEt, CH2Cl2; (e) LiAlH4, THF, 0 °C.
Scheme 2. Reagents and conditions: (a) t-BuONa, n-BuOH, lwave, 150 °C, 1 h; (b) 4-BrC6H4SO2Cl, Et3N, CH2Cl2, rt.
beads and a microscintillation plate reader.36 Biochemical assays
used recombinant 11b-HSD1 isolated as a microsomal preparation
from transfected CHO cells. Assays were performed in 25 mM
HEPES, pH 7.4, 50 mM KCl, 2.5 mM NaCl, 1 mM MgCl2, 1 mM
NADPH and 80 nM [3H]-cortisone at room temperature for 1 h.
Cell-based potency was assessed in differentiated human adipo-
cytes by the addition of cortisone (80 nM [3H]-cortisone) to the cell
culture medium and incubation at 37 °C for 2 h. IC50 values repre-
sent the mean of at least duplicate assays and were generated from
an 8-point dose-response curve.
Benzyl (6b–6d) and phenyl (6e–6g) groups substituted on all
three positions of the piperidine ring of 6a were able to fill Pocket
II and improved enzyme potency to <2.5 nM (Table 1). ContourTM
generated models indicated that 3-benzylpiperidine 6c could be
constrained into spirocycle 6h and 4-phenylpiperidine urea 6g
could be constrained into spirocycle 6i, both of which retained po-
tency while providing rigid frameworks on which to append sub-
stitution.37 While the enzyme potencies of 6b–6i were attractive,
their lipophilicity was higher than desirable for drug-like mole-
cules. For example, compound 6i has c log D = 4.35 and polar sur-
face area of only 32 Å2. The main goal for medicinal chemistry
Figure 4. Overlap of carbenoxolone 1 and urea 10j2 in the binding site of 11b-
HSD1. The protein structure, pose of 1 and crystallographic waters are taken from
2bel. The carbon atoms of 1 are depicted in gold. A model of 10j2, generated by
ContourTM, is depicted in green. A change in the conformation of Tyr177 was
necessary to accommodate 10j2.
became lowering c log D and improving water solubility by intro-
duction of polar groups into the molecule. To avoid introducing a

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C. M. Tice et al. / Bioorg. Med. Chem. Lett. 20 (2010) 881–886
Table 2
SAR of spirocyclic ureas 10
R
3
2
4
H
5
X
N
N
7
6
O
10
R
X
Enzyme IC50 (nM)
Adipocyte IC50 (nM)
11b-HSD2 (nM)
e
6i
H
CO2H
H
H
H
H
0.8
68.6
16.1
39.9
16.5
3.4
6.7
8.9
7.6
3.4
3.4
2.2
1.6
2.0
1.1
2.0
0.5
1.7
2.7
e
10a
10b
10b1a
10b2b
10c
10d
10e
10f
>200
60.3
193.5
57.8
19.7
49.1
22.5
18.3
23.2
30.2
10.7
5.3
7.5
2.5
22.3
0.9
18.0
CH2CO2H
CH2CO2H
CH2CO2H
CH2CO2H
CH2CO2H
CH2CO2H
CH2CO2H
CH2CO2H
CH2CO2H
CH2CO2H
CH2CO2H
CH2CO2H
CH2CO2H
CH2CONHSO2Me
CH2CONH2
CH2CH2OH
>10,000
5,900
21,200
510
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
H
4-Me
5-Me
6-Me
7- Me
5-Cl
6-Cl
7-Cl
7-Br
7-Br
7-Br
7-Br
7-Br
7-Br
10g
10h
10i
10j
10j1c
10j2d
10k
10l
>10,000
e
10m
9,000
a
Stereochemical configuration unknown: derived from enantiomer of methyl ester 9b with shorter retention time on a Chiral Technologies ODH column eluted with a
90:10 hexane/i-PrOH mixture containing 0.22% Et2NH.
b
Stereochemical configuration unknown: derived from enantiomer of methyl ester 9b with longer retention time on a Chiral Technologies ODH column eluted with a
90:10 hexane/i-PrOH mixture containing 0.22% Et2NH.
c
S isomer.
R isomer.
Not tested.
d
e
chiral center, we elected to make further modifications on the 4-
substituted piperidine derivatives 6g and 6i.
parameters of 10b are shown in Table 3. The compound was
rapidly absorbed and had high oral bioavailability but was sub-
ject to rapid clearance. Chiral chromatography of the methyl es-
ter precursor 9b permitted characterization of the individual
enantiomers of 10b. Although isomer 10b2, derived from the
methyl ester with the longer retention time, was slightly more
potent in the adipocyte assay than its enantiomer 10b1, the sim-
ilar activity of the two enantiomers is consistent with our model
in which the acetic acid side chain is accommodated in the sol-
vent channel.
Examination of the models of both enantiomers of 10b bound to
the protein suggested that small lipophilic substituents would be
tolerated at the 4-, 5-, 6- and 7-positions on the fused benzene ring
which occupies Pocket II. The 7-position looked especially favor-
able since a suitable hydrophobic substituent at this position
should pack against the hydrophobic residues Leu126 and Val180
and occupy a similar position to the methyl group in the 8-position
of carbenoxolone. Appending methyl groups at the 4-, 5-, 6- and 7-
Initial attempts to introduce polar functionality at the 4-posi-
tion of 6g led to less potent analogs 6j and 6k. This was consistent
with our model in which the OH and CONH2 groups of 6j and 6k lie
within a hydrophobic region of the binding site. Comparison of the
model of spirocycle 6i bound to 11b-HSD1 with the X-ray structure
of carbenoxolone (1) indicated that a carboxylic acid could be ap-
pended to C3 of the ethylene bridge of the spirocycle and reach the
same water channel region as the succinate carboxylate of carben-
oxolone (Fig. 4). In addition to imparting water solubility, a carbox-
ylate functionality was anticipated to reduce target promiscuity.38
On the other hand, carboxylic acids are frequently highly protein
bound.39
Direct attachment of a carboxylic acid at C3 reduced enzyme
potency by almost 100Â (10a vs 6i, Table 2); however, when an
acetic acid moiety was appended at this position a less drastic
20Â reduction in potency was observed (10b vs 10i). Rat PK
Table 3
Pharmacokinetic data for 10b and 10ja,b,c
Table 4
Mouse tissue distribution of 10j and 10j2a
Compound
Species
AUC(inf)
t1/2
IV CL
F
(ng h/mL)
(h)
(mL/min kg)
(%)
Compound Drug level in liver Drug level in
Drug level in
(ng/mL)
adipose (ng/mL)
plasma (ng/mL)
10b
10j
10j
10j
Ratc
3532
5397
1718
743
2.87
3.46
6.17
6.03
47.1
26.6
28.1
13.8
94
90
29
31
Ratc
10j
10j2
5130
7067
77
127
442
393
Mousec
Monkeyd
a
Animals (n = 3) were dosed PO with 30 mg/kg suspended in 0.5% methocellu-
a
b
c
Oral PK parameters are shown unless otherwise stated.
Compounds were dosed as sodium salts.
Dose: 9.68 mg/kg PO; 1.9 mg/kg IV.
lose in PBS. Tissues were harvested at 4 h and snap frozen. Later, thawed tissues
were homogenized in 0.05 M BES, pH 7, and compound was extracted into aceto-
nitrile. Concentrations were determined by LC–MS/MS, by comparison to a standard
curve generated independently in each tissue matrix.
d
Dose: 2 mg/kg PO, 1 mg/kg IV.

C. M. Tice et al. / Bioorg. Med. Chem. Lett. 20 (2010) 881–886
885
60
50
40
30
20
10
0
Vehicle
10j2
-2.0
0.0
2.0
4.0
6.0
8.0
10.0
Time (h)
Figure 5. Pharmacodynamic effects of 10j2 in cynomolgus monkeys. In this model, the animals were dosed with dexamethasone 8 h prior to compound administration
(t = À8 h) to suppress endogenous plasma cortisol concentrations. The animals, then, received vehicle or compound (10 mg/kg, PO) at time zero (t = 0 h) and two hours later
(t = 2 h), were challenged with cortisone 21-acetate (25 mg, PO). Blood samples were drawn every 30 min for 6 h to measure cortisol levels. The animals were crossed over
after a seven day washout.
positions (10c–10f) improved enzyme potency in all cases; how-
ever, methyl substitution at the 4-position led to an increase in
11b-HSD2 activity. Chlorine substitution had a favorable effect on
potency at the 5-, 6- and, especially, 7-positions (10g–10i). Instal-
lation of a bromine at the 7-position gave 10j with an IC50 of
1.6 nM in the enzyme assay and 5.3 nM in the cellular assay, a
2Â improvement over the 7-chloro compound 10i. Subsequently,
the enantiomers of 10j were separated and assayed individually:
the R isomer, 10j2, proved to be 3Â more potent than the S isomer,
10j1, in adipocytes. Three derivatives of the carboxylic acid moiety
in 10j were prepared. Introduction of the weakly acidic acylsulf-
onamide group in 10k decreased cellular potency. In the neutral
acetamide derivative 10l, increased enzyme and cellular potency
were demonstrated, while hydroxyethyl compound 10m was less
potent than 10j in cells.
orally bioavailable in three species, distributes into adipose tissue
in the mouse, and significantly inhibits 11b-HSD1 in a primate
pharmacodynamic model.
References and notes
1. Wamil, M.; Seckl, J. R. Drug Discovery Today 2007, 12, 504.
2. Fotsch, C.; Wang, M. J. Med. Chem. 2008, 51, 4851.
3. Saiah, E. Curr. Med. Chem. 2008, 15, 642.
4. Walker, B. R.; Andrew, R. Ann. N.Y. Acad. Sci. 2006, 1083, 165.
5. Tomlinson, J. W.; Stewart, P. M. Best Pract. Res., Clin. Endocrinol. Metab. 2007, 21,
607.
6. Masuzaki, H.; Paterson, J.; Shinyama, H.; Morton, N. M.; Mullins, J. J.; Seckl, J. R.;
Flier, J. S. Science (Washington, DC, U. S.) 2001, 294, 2166.
7. Masuzaki, H.; Yamamoto, H.; 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, 112, 83.
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. Proc.
Natl. Acad. Sci. U.S.A. 1997, 94, 14924.
9. Morton, N. M.; Holmes, M. C.; Fievet, C.; Staels, B.; Tailleux, A.; Mullins, J. J.;
Seckl, J. R. J. Biol. Chem. 2001, 276, 41293.
10. 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.
11. Andrews, R. C.; Rooyackers, O.; Walker, B. R. J. Clin. Endocrinol. Metab. 2003, 88,
285.
Bromo compound 10j was selected for advanced in vitro evalu-
ation. The c log D of 10j is 3.1 and its PSA is 70 Å2. It was >1000Â
selective for 11b-HSD1 over three other steroid dehydrogenases:
3b -HSD2, 11b-HSD2 and 17b-HSD2. Its IC50 values against recom-
binant CYP3A4, CYP2C9 and CYP2D6 were >15 lM, and its half-life
in human liver microsomes was >1 h. The single enantiomer 10j2
12. Sandeep, T. C.; Andrew, R.; Homer, N. Z. M.; Andrews, R. C.; Smith, K.; Walker,
B. R. Diabetes 2005, 54, 872.
13. Barf, T.; Vallgårda, 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.; Abrahmsen, L. J. Med. Chem. 2002, 45,
3813.
14. St. Jean, D. J., Jr.; Wang, M.; Fotsch, C. Curr. Top. Med. Chem. (Sharjah, United Arab
Emirates) 2008, 8, 1508.
15. Boyle, C. D. Curr. Opin. Drug Disc. Dev. 2008, 11, 495.
16. Schnackenberg, C. G. Curr. Opin. Invest. Drugs (Thomson Sci.) 2008, 9, 295.
17. 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. J. Exp. Med. 2005, 202, 517.
18. Sundbom, M.; Kaiser, C.; Bjoerkstrand, E.; Castro, V. M.; Larsson, C.; Selen, G.;
Nyhem, C. S.; James, S. R. BMC Pharmacol. 2008, 8.
19. Hale, C.; Veniant, M.; Wang, Z.; Chen, M.; McCormick, J.; Cupples, R.; Hickman,
D.; Min, X.; Sudom, A.; Xu, H.; Matsumoto, G.; Fotsch, C.; St. Jean, D. J., Jr.;
Wang, M. Chem. Biol. Drug Des. 2008, 71, 36.
20. Bhat, B. G.; Hosea, N.; Fanjul, A.; Herrera, J.; Chapman, J.; Thalacker, F.; Stewart,
P. M.; Rejto, P. A. J. Pharmacol. Exp. Ther. 2008, 324, 299.
did not significantly inhibit or bind to a panel of 68 receptors
and
ion
channels
in
the
MDS
Pharma
Services
LeadProfilingScreenÒ.
Compound 10j was profiled in pharmacokinetic (PK) and in
pharmacodynamic (PD) studies in vivo: 10j had high bioavailabil-
ity (%F = 90) and moderate clearance (26.6 mL/min.kg) in the rat
(Table 3). Oral bioavailability was more modest in mouse
(%F = 29) and monkey (%F = 31). Tissue distribution studies in mice
showed that after oral administration of 10j and 10j2 (30 mg/kg),
compound was detected in adipose and liver, the key target tissues
(Table 4).40 Compound 10j2 was tested in a cynomolgus monkey
PD model using a crossover design (n = 5 animals). When dosed
PO at 10 mg/kg, 10j2 reduced the plasma concentration of cortisol
ꢀ80% (Fig. 5), consistent with significant inhibition of 11b-HSD1, in
vivo.
We have described the structure guided discovery of 10j2, a po-
tent and selective inhibitor of 11b-HSD1, in vitro. This compound is

886
C. M. Tice et al. / Bioorg. Med. Chem. Lett. 20 (2010) 881–886
21. Xiang, J.; Wan, Z.-K.; Li, H.-Q.; Ipek, M.; Binnun, E.; Nunez, J.; Chen, L.; McKew, J.
C.; Mansour, T. S.; Xu, X.; Suri, V.; Tam, M.; Xing, Y.; Li, X.; Hahm, S.; Tobin, J.;
Saiah, E. J. Med. Chem. 2008, 51, 4068.
22. Wan, Z.-K.; Chenail, E.; Xiang, J.; Li, H.-Q.; Ipek, M.; Bard, J.; Svenson, K.; Mansour,
T. S.; Xu, X.; Tian, X.; Suri, V.; Hahm, S.; Xing, Y.; Johnson, C. E.; Li, X.; Qadri, A.;
Panza, D.; Perreault, M.; Tobin, J. F.; Saiah, E. J. Med. Chem. 2009, 52, 5449.
23. Wang, Z.; Wang, M. Curr. Chem. Biol. 2009, 3, 159.
Sudom, A.; Sun, D.; Tu, H.; Ursu, S.; Walker, N.; Yan, X.; Ye, Q.; Powers, J. P. J.
Med. Chem. 2008, 51, 3953.
30. Fotsch, C.; Bartberger, M. D.; Bercot, E. A.; Chen, M.; Cupples, R.; Emery, M.;
Fretland, J.; Guram, A.; Hale, C.; Han, N.; Hickman, D.; Hungate, R. W.; Hayashi,
M.; Komorowski, R.; Liu, Q.; Matsumoto, G.; St. Jean, D. J.; Ursu, S.; Veniant, M.;
Xu, G.; Ye, Q.; Yuan, C.; Zhang, J.; Zhang, X.; Tu, H.; Wang, M. J. Med. Chem. 2008,
51, 7953.
24. Maser, E.; Voelker, B.; Friebertshaeuser, J. Biochemistry 2002, 41, 2459.
25. Patel, J. R.; Shuai, Q.; Dinges, J.; Winn, M.; Pliushchev, M.; Fung, S.; Monzon, K.;
Chiou, W.; Wang, J.; Pan, L.; Wagaw, S.; Engstrom, K.; Kerdesky, F. A.;
Longenecker, K.; Judge, R.; Qin, W.; Imade, H. M.; Stolarik, D.; Beno, D. W. A.;
Brune, M.; Chovan, L. E.; Sham, H. L.; Jacobson, P.; Link, J. T. Bioorg. Med. Chem.
Lett. 2007, 17, 750.
31. 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.
Bioorg. Med. Chem. Lett. 2005, 15, 4359.
32. Patel, J. R.; Shuai, Q.; Link, J. T.; Rohde, J. J.; Dinges, J.; Sorensen, B. K.; Winn, M.;
Yong, H.; Yeh, V. S. WO200607424.
26. Johansson, L.; Fotsch, C.; Bartberger, M. D.; Castro, V. M.; Chen, M.; Emery, M.;
Gustafsson, S.; Hale, C.; Hickman, D.; Homan, E.; Jordan, S. R.; Komorowski, R.;
Li, A.; McRae, K.; Moniz, G.; Matsumoto, G.; Orihuela, C.; Palm, G.; Veniant, M.;
Wang, M.; Williams, M.; Zhang, J. J. Med. Chem. 2008, 51, 2933.
27. Wang, H.; Ruan, Z.; Li, J. J.; Simpkins, L. M.; Smirk, R. A.; Wu, S. C.; Hutchins, R.
D.; Nirschl, D. S.; Van Kirk, K.; Cooper, C. B.; Sutton, J. C.; Ma, Z.; Golla, R.;
Seethala, R.; Salyan, M. E. K.; Nayeem, A.; Krystek, S. R., Jr.; Sheriff, S.; Camac, D.
M.; Morin, P. E.; Carpenter, B.; Robl, J. A.; Zahler, R.; Gordon, D. A.; Hamann, L.
G. Bioorg. Med. Chem. Lett. 2008, 18, 3168.
28. Sun, D.; Wang, Z.; Di, Y.; Jaen, J. C.; Labelle, M.; Ma, J.; Miao, S.; Sudom, A.; Tang,
L.; Tomooka, C. S.; Tu, H.; Ursu, S.; Walker, N.; Yan, X.; Ye, Q.; Powers, J. P.
Bioorg. Med. Chem. Lett. 2008, 18, 3513.
29. Julian, L. D.; Wang, Z.; Bostick, T.; Caille, S.; Choi, R.; DeGraffenreid, M.; Di, Y.;
He, X.; Hungate, R. W.; Jaen, J. C.; Liu, J.; Monshouwer, M.; McMinn, D.; Rew, Y.;
33. Linders, J. T. M.; Willemsens, G. H. M.; Gilissen, R. A. H. J.; Buyck, C. F. R. N.;
Vanhoof, G. C. P.; Van Der Veken, L. J. E.; Jaroskova, L. WO 2004056744.
34. Cheng, H.; Smith, C. R.; Wang, Y.; Parrott, T. J.; Dress, K. R.; Nair, S. K.; Hoffman,
J. E.; Le, P. T. Q.; Kupchinsky, S. W.; Yang, Y.; Cripps, S. J.; Huang, B.
WO2005108359.
35. Spiropiperidines 8 were purchased from WuXi AppTec, Shanghai, China.
36. Solly, K.; Mundt, S. S.; Zokian, H. J.; Ding, G. J.-F.; Hermanowski-Vosatka, A.;
Strulovici, B.; Zheng, W. Assay Drug Dev. Technol. 2005, 3, 377.
37. Lepifre, F.; Christmann-Franck, S.; Roche, D.; Leriche, C.; Carniato, D.; Charon,
C.; Bozec, S.; Doare, L.; Schmidlin, F.; Lecomte, M.; Valeur, E. Bioorg. Med. Chem.
Lett. 2009, 19, 3682.
38. Leeson, P. D.; Springthorpe, B. Nat. Rev. Drug Disc. 2007, 6, 881.
39. Gleeson, M. P. J. Med. Chem. 2007, 50, 101.
40. Stewart, P. M.; Tomlinson, J. W. Diabetes 2009, 58, 14.