Azabicyclic sulfonamides as potent 11β-HSD1 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2010.01.082

Inhibition of 11β-HSD1 has demonstrated potential in the treatment of various components of metabolic syndrome. We wish to report herein the discovery of novel azabicyclic sulfonamide based 11β-HSD1 inhibitors. Highly potent compounds exhibiting inhibitor

Full text of DOI:10.1016/j.bmcl.2010.01.082

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1551–1554
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Azabicyclic sulfonamides as potent 11b-HSD1 inhibitors q
a
a
b
a
Unmesh Shah a, , Craig D. Boyle , Samuel Chackalamannil , Hana Baker , Timothy Kowalski ,
*
Julie Lee a, Giuseppe Terracina a, Lili Zhang a
a Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
b BioTechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, IN 46285, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Inhibition of 11b-HSD1 has demonstrated potential in the treatment of various components of metabolic
syndrome. We wish to report herein the discovery of novel azabicyclic sulfonamide based 11b-HSD1
inhibitors. Highly potent compounds exhibiting inhibitory activities at both human and mouse 11b-
HSD1 were identified. Several compounds demonstrated significant in vivo activity in the mouse corti-
sone challenge assay.
Received 2 December 2009
Revised 13 January 2010
Accepted 14 January 2010
Available online 25 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
11b-HSD1
Glucocorticoids
Inhibitor
Metabolic syndrome
Type 2 diabetes
Glucocorticoids are steroid hormones that regulate glucose
metabolism, cardiovascular homeostasis, CNS modulation, inflam-
mation, and immune function.1 Elevated glucocorticoid levels are
associated with obesity, diabetes, hypertension, dyslipidemia,
mood disorders, memory impairment, and increased cardiovascu-
lar risks.2,3 Cortisol is an important human glucocorticoid, which
upon binding to the glucocorticoid receptor regulates several phys-
iological events.4 11b-Hydroxysteroid dehydrogenase (11b-HSD)
catalyzes the interconversion of active cortisol and inert cortisone
(Fig. 1), thereby protecting the glucocorticoid receptor from gluco-
corticoid excess.2 Two isozymes of 11b-HSD have been isolated,
each of which influence intracellular glucocorticoid levels.5 11b-
HSD2 inactivates cortisol (by converting it to inactive cortisone),
thereby protecting key tissues. By contrast, 11b-HSD1 regenerates
the active cortisol, resulting in enhanced glucocorticoid effects.
Consequently, inhibition of 11b-HSD1 is a potential therapeutic
target for glucocorticoid-associated metabolic and CNS disor-
ders.2,6,7 Here we wish to report the discovery of potent 11b-
HSD1 inhibitors for the treatment of diabetes, obesity, and related
metabolic disorders.
indications.6,7 Selectivity over 11b-HSD2 is usually not an issue
since the amino acid sequence of 11b-HSD1 is approximately 14%
identical to that of 11b-HSD2.8 However, there is a difference in the
sequence homology between the human and rodent 11b-HSD1 en-
zyme, which has presented some difficulties in identifying com-
pounds that are equipotent towards human and rodent 11b-
Figure 1. Interconversion of cortisone and cortisol via 11b-HSD1 and 11b-HSD2.
Several classes of 11b-HSD1 inhibitors have been described in
the literature for the treatment of metabolic syndrome and other
q
All the authors were Schering-Plough employees at the time this research was
conducted. Since then Schering-Plough has been acquired by Merck and Co.
Address: Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth,
NJ 07033, USA.
* Corresponding author. Tel.: +1 908 740 5323; fax: +1 908 740 7164.
E-mail address: unmesh.shah@spcorp.com (U. Shah).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.01.082
Figure 2. Early prototypical 11b-HSD1 inhibitors.

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U. Shah et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1551–1554
HSD1.9 Some of the earlier reported 11b-HSD1 inhibitors were thi-
azole analogs containing an appropriately substituted sulfonamide
moiety (e.g., 1, Fig. 2).10 Another striking structural feature in
several published potent and selective 11b-HSD1 inhibitors was
the presence of a lipophilic carbocycle, such as an adamantane
group (e.g., 2, Fig. 2).7,11 Our plan was to combine these two struc-
tural features in a single molecule and towards this rationale we
decided to explore azabicyclic sulfonamides containing lipophilic
substituents as potential 11b-HSD1 inhibitors.
Table 1
SAR of N-methyl-2,5-diaza-bicyclo[2.2.1]heptane based aryl-sulfonamide analogs as
11b-HSD1 inhibitors
Compound #
R
11b-HSD1 hIC50
(
lM) 11b-HSD1 mIC50 (lM)
Our SAR efforts began with the exploration of substituted 2,5-
diaza-bicyclo[2.2.1]heptane analogs prepared as shown in
Scheme 1. N-Methylation of (1S,4S)-tert-butyl-2,5-diazabicyclo-
[2.2.1]heptane-2-carboxylate (3) with sodium hydride and iodo-
methane, followed by deprotection of the tert-butylcarbamate
group provided the free amine intermediate 5. Treatment of this
intermediate with commercially available arylsulfonyl chlorides
in the presence of Hünig’s base provided the corresponding 2,5-
diaza-bicyclo[2.2.1]heptane based aryl-sulfonamide derivatives.
The in vitro human and mouse 11b-HSD1 inhibitory activities are
summarized in Table 1.12 Our earlier SAR from a structurally re-
lated series had shown para-substitution on the aryl ring to be pre-
ferred and the tert-butyl group was identified as an optimal group
at this position.13 Incorporating this finding in the 2,5-diaza-bicy-
clo[2.2.1]heptane series resulted in 7, which was close to satisfying
our criteria of human 11b-HSD1 IC50 < 100 nM (7: hIC50 = 109 nM).
This compound also demonstrated promising mouse 11b-HSD1
inhibition in vitro. Replacement of the tert-butyl group with other
alkyl groups (8, 9) resulted in diminished activity and alkoxy or
halogen substitution rendered the compounds (10, 11) close to
inactive against 11b-HSD1.
7
8
9
10
11
tBu
Neopentyl
Et
OMe
Cl
0.11
0.33
3.30
16.1
11.3
0.36
0.26
3.09
8.88
12.1
The 4-tert-butyl-phenylsulfonyl group was retained as the pre-
ferred sulfonamide moiety and further SAR was conducted by
exploring substitution at the opposite nitrogen as shown in
Scheme 2. Treatment of (1S,4S)-tert-butyl-2,5-diazabicyclo[2.2.1]-
heptane-2-carboxylate (3) with 4-tert-butylbenzene-1-sulfonyl
chloride in the presence of Hünig’s base provided intermediate
12. Interestingly, the tert-butyl carbamate functionality was toler-
ated, however the compound was about threefold less potent at
human 11b-HSD1 compared to the initial lead 7 (Table 2). Removal
of the Boc group resulted in the free amine 13, which demon-
strated a substantial loss in the human 11b-HSD1 activity. To fur-
ther expand upon our initial plan to incorporate lipophilicity we
explored cycloalkyl substituents at this amino position. Reductive
alkylation of 13 with cycloalkanones in the presence of sodium tri-
acetoxyborohydride afforded the corresponding 2,5-diazabicy-
clo[2.2.1]heptane analogs (14).
Scheme 2. Synthesis of 2,5-diaza-bicyclo[2.2.1]heptane based sulfonamide analogs
containing N-cycloalkyl substituents. Reagents and conditions: (a) ArSO2Cl, DIPEA,
CH2Cl2, where Ar = 4-tBu-phenyl; (b) TFA, CH2Cl2; (c) sodium triacetoxyborohy-
dride, ketones, dichloroethane, 100 °C.
Table 2
SAR of 2,5-diaza-bicyclo[2.2.1]heptane based sulfonamide analogs
The nor-camphor derived analogs 15 and 16 (stereochemistry
not established) demonstrated human and mouse 11b-HSD1
Compound
#
–R
11b-HSD1 hIC50
(nM)
11b-HSD1 mIC50
(nM)
12
13
COOtBu
–H
361
4402
772
156
15
16
75
77
31
8
isomer-1
isomer-2
17
18
118
40
79
1
IC50 < 100 nM. While the cyclohexyl analog 17 was somewhat less
active, the corresponding cyclopentyl analog 18 was the most
promising compound in this series (hIC50 = 40 nM, mIC50 = 1 nM)
Scheme 1. Synthesis of N-methyl-2,5-diaza-bicyclo[2.2.1]heptane based aryl-sul-
fonamide analogs. Reagents and conditions: (a) 60% NaH, MeI, THF; (b) TFA, CH2Cl2;
(c) ArSO2Cl, DIPEA, CH2Cl2.

U. Shah et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1551–1554
1553
Table 3
Table 4
SAR of 3,8-diaza-bicyclo[3.2.1]octane based sulfonamide analogs
SAR of C3 substituted 8-(4-tbutylphenylsulfonyl)-8-azabicyclo[3.2.1]octane analogs
X
Y
N
S
O
O
Compound
#
–X
–Y
11b-HSD1 hIC50
(nM)
11b-HSD1 mIC50
(nM)
28
29
OH (or
Ph)
OH (or
Bn)
OH
OMe
OH
OMe
OH
OMe
H
H
H
CF3
Ph (or
OH)
Bn (or
OH)
H
H
Me
Me
CF3
CF3
OH
OMe
OEt
OH
1623
740
138
114
Compound # –R
11b-HSD1 hIC50 (nM) 11b-HSD1 mIC50 (nM)
19
20
21
–H
–Boc
–Me
547
309
478
54
692
117
30
31
32
33
34
35
36
37
38
39
40
30
69
19
28
8
41
13
3
32
5
5
14
22
137
3
276
356
970
37
114
32
2
206
43
CF3
OMe
48
and plasma cortisol levels were determined one hour subse-
quently.14,15 Unfortunately, the cyclopentyl analog 18 failed to
demonstrate in vivo activity, presumably due in part to the suscep-
tibility of unsubstituted cycloalkyl groups to undergo oxidative
metabolism.
Simultaneously we explored 3,8-diaza-bicyclo[3.2.1]octane
analogs, which were synthesized in a similar manner as their bicy-
clo[2.2.1]heptane counterparts. The 4-tert-butylphenyl sulfon-
amide motif was retained and SAR at the opposite nitrogen
(Table 3) demonstrated the cyclopentyl group to be the optimal
aza-substituent. Although compound 22 exhibited a single digit
mIC50, the criteria of hIC50 < 100 nM was not achieved and hence
it was not tested further.
8-Aza-bicyclo[3.2.1]octane analogs were prepared next as
shown in Scheme 3. Base mediated sulfonylation of the commer-
cially available (1R,5S)-8-azabicyclo[3.2.1]octan-3-one with 4-
tert-butylbenzene-1-sulfonyl chloride provided the sulfonamide
intermediate 24. Using the 4-tert-butylphenyl sulfone as the N-
capping group, several modifications at the C3 position were ex-
plored. The ketone functionality in 24 was subjected to nucleo-
philic attack resulting in the desired hydroxyl analogs (25).
Alkylation of 25 in the presence of sodium hydride furnished the
corresponding alkoxy derivatives (26). Although a clear SAR-trend
could not be established (Table 4), it was clear that larger substit-
uents were not tolerated in this region (28, 29). Substitution at this
position with a smaller substituent such as a hydroxyl, alkyl, or
Scheme 3. Synthesis of 8-aza-bicyclo[3.2.1]octane derivatives. Reagents and con-
ditions: (a) ArSO2Cl, DIPEA, CH2Cl2, where Ar = 4-tBu-phenyl; (b) sodium borohy-
dride, methanol; (c) RMgBr, THF or CF3ꢀTMS, TBAF, THF, 0 °C to rt; (d) NaH, R0I, DMF;
(e) NH2ORꢀHCl, pyridine.
and was studied in vivo. The in vivo assay was a mouse cortisone
challenge in which the animals were orally dosed with a solution
of dexamethasone and either the test agent or the vehicle (20%
HPbCD). One hour later cortisone was administered (1 mg/kg, sc)
Figure 3. Activities of selected 11b-HSD1 inhibitors in an in vivo mouse cortisone challenge assay. Compound 44,
a known 11b-HSD1 inhibitor, was used for
comparison.14,15b

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U. Shah et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1551–1554
Table 5
References and notes
8-(4-tButylphenylsulfonyl)-8-azabicyclo[3.2.1]octane series: SAR of C3 oxime analogs
1. Atanasov, A. G.; Odermatt, A. Endocr. Metab. Immune Disord. Drug Targets 2007,
7, 125.
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3. Newell-Price, J.; Bertagna, X.; Grossman, A. B.; Nieman, L. K. Lancet 2006, 367,
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U. C.; Persson, B.; Jörnvall, H. Eur. J. Biochem. 1997, 249, 355.
6. (a) Boyle, C. D.; Kowalski, T. J.; Zhang, L. Annu. Rep. Med. Chem. 2006, 41, 127;
(b) Boyle, C. D. Curr. Opin. Drug Discov. Devel. 2008, 11, 495.
7. Boyle, C. D.; Kowalski, T. J. Expert Opin. Ther. Patents 2009, 19, 801.
8. Albiston, A. L.; Obeyesekere, V. R.; Smith, R. E.; Krozowski, Z. S. Mol. Cell.
Endocrinol. 1994, 105, R11.
Compound #
R
11b-HSD1 hIC50 (nM)
11b-HSD1 mIC50 (nM)
41
42
43
Bn
Me
H
159
860
270
989
103
47
9. Barf, T.; Williams, M. Drugs Future 2006, 31, 231.
10. Barf, T.; Vallgårda, J.; Emond, R.; Häggström, C.; Kurz, G.; Nygren, A.; Larwood,
V.; Mosialou, E.; Axelsson, K.; Olsson, R.; Engblom, L., et al. J. Med. Chem. 2002,
45, 3813.
11. 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.,
et al. J. Exp. Med. 2005, 202, 517.
alkoxy group was found to be more favorable. Several compounds
with hIC50 < 50 nM and mIC50 < 10 nM were identified and a se-
lected few were evaluated in vivo (Fig. 3). The hydroxyl analog
30 demonstrated equipotent human and mouse 11b-HSD1 inhibi-
tion in vitro, and showed modest activity in the mouse cortisone
challenge assay (24%I @ 30 mpk).14,15 On the other hand, com-
pounds 31 and 37, which possessed single digit mIC50, demon-
12. The in vitro assays were performed under the following conditions: (a) Preparation
of 11b-HSD1 membranes. Human and mouse 11b-HSD1 with N-terminal
myctag was expressed in Sf9 cells using baculovirus Bac-to-Bac expression
system (Invitrogen) according to manufacturer’s instructions. Cells were
harvested three days after infection and washed in PBS before frozen. To
make membranes, the cells were resuspended in buffer A (20 mM Tris–HCl, pH
7.4, 100 mM NaCl, 2 mM EDTA, 2 mM EGTA and Complete™ protease inhibitor
tablets (Roche Molecular Biochemicals), and lysed in a nitrogen bomb at
900 psi. The cell lysate was centrifuged at 600 g for 10 min to remove nuclei
and large cell debris. The supernatant was centrifuged at 100,000 g for 1 h. The
membrane pellet was resuspended in buffer A, flash-frozen in liquid nitrogen
and stored at ꢁ70 °C before use. (b) Measurement of 11b-HSD1 activity. Human
strated better mouse efficacy (40% and 57%I
@ 30 mpk,
respectively). We also explored selected C3 oxime analogs (27,
Scheme 3), which demonstrated somewhat diminished 11b-HSD1
inhibition (Table 5).
In summary, potent 11b-HSD1 inhibitors were identified in three
azabicyclic sulfonamide series. Several compounds demonstrated
significant activity in the mouse cortisone challenge assay. In the
bridged piperazine series, 18 was the most promising analog having
mouse IC50 = 1 nM and human IC50 = 40 nM. In the 8-aza-bicy-
clo[3.2.1]octane series, 37 was the lead compound (hIC50 = 37 nM,
mIC50 = 5 nM), which demonstrated good 11b-HSD1 inhibition
in vivo (57%I @ 30 mpk). Further evaluation of these and other re-
lated analogs along with additional SAR exploration will be reported
in due course.
and mouse 11b-HSD1 enzymatic activity was measured in a 50
containing 20 mM NaPO4 pH 7.5, 0.1 mM MgCl2, 3 mM NADPH (prepared fresh
daily), 125 nM 3H-cortisone (American Radiochemicals) and 0.5
g membrane.
The reaction was incubated at room temperature for 1 h before it was stopped
by addition of 50 M buffer containing 20 mM NaPO4 pH 7.5, 30 M 18b-
glycyrrhetinic acid, 1 g/ml monoclonal anti-cortisol antibody (Biosource) and
lL reaction
l
l
l
l
2 mg/ml antimouse antibody coated scintillation proximity assay (SPA) beads
(Amersham Bioscience). The mixture was incubated at room temperature for
2 h with vigorous shaking and analyzed on a Top Count scintillation counter.
13. Lankin, C. M.; Boyle, C. D.; Chackalamannil, S.; Shah, U.; Baker, H.; Kowalski, T.;
Zhang, L.; Terracina, G. Abstracts of Papers, 234th National Meeting of the
American Chemical Society, Boston, MA, Aug 19–23, 2007; American Chemical
Society: Washington, DC, 2007; MEDI 052.
14. The in vivo activity was compared to that of the published 11b-HSD1 inhibitor
44, which demonstrated approximately 40–45% inhibition in the mouse
cortisone challenge assay described herein.
Acknowledgments
The authors would like to thank Drs. William Greenlee, John
Piwinski, Michael Graziano, and Catherine Strader for their valu-
able input. Also acknowledged are Drs. Pradeep Das and Tze-Ming
Chan for obtaining analytical data. The authors also thank Ms. Ana
Bercovici for providing some intermediates used herein.
15. (a) Shah, U.; Boyle, C. D.; Chackalamannil, S. WO Patent 2009023180, 2009; (b)
Balkovec, J. M.; Thieringer, R.; Mundt, S. S.; Hermanowski-Vosatka, A.; Graham,
D. W.; Patel, G. F.; Aster, S. D.; Waddell, S. T.; Olson, S. H.; Maletic, M. WO
Patent 2003065983, 2003.