Pyridine amides as potent and selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1

Article abstract of DOI:10.1016/j.bmcl.2008.04.069

Several series of pyridine amides were identified as selective and potent 11β-HSD1 inhibitors. The most potent inhibitors feature 2,6- or 3,5-disubstitution on the pyridine core. Various linkers (CH₂SO₂, CH₂S, CH₂

Full text of DOI:10.1016/j.bmcl.2008.04.069

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 3168–3172
Pyridine amides as potent and selective inhibitors
of 11b-hydroxysteroid dehydrogenase type 1
Haixia Wang,a,* Zheming Ruan,b,* James J. Li,a Ligaya M. Simpkins,a Rebecca A. Smirk,a
Shung C. Wu,a Robert D. Hutchins,b David S. Nirschl,b Katy Van Kirk,b
Christopher B. Cooper,b James C. Sutton,a Zhengping Ma,a Rajasree Golla,a
Ramakrishna Seethala,a Mary Ellen K. Salyan,a Akbar Nayeem,a Stanley R. Krystek, Jr.,a
Steven Sheriff,b Daniel M. Camac,b Paul E. Morin,b Brian Carpenter,b
Jeffrey A. Robl,a Robert Zahler,a David A. Gordona and Lawrence G. Hamanna
aBristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08543-5400, USA
bBristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA
Received 8 March 2008; revised 18 April 2008; accepted 28 April 2008
Available online 1 May 2008
Abstract—Several series of pyridine amides were identified as selective and potent 11b-HSD1 inhibitors. The most potent inhibitors
feature 2,6- or 3,5-disubstitution on the pyridine core. Various linkers (CH2SO2, CH2S, CH2O, S, O, N, bond) between the distal
aryl and central pyridyl groups are tolerated, and lipophilic amide groups are generally favored. On the distal aryl group, a number
of substitutions are well tolerated. A crystal structure was obtained for a complex between 11b-HSD1 and the most potent inhibitor
in this series.
Ó 2008 Elsevier Ltd. All rights reserved.
The enzyme 11b-hydroxysteroid dehydrogenase type 1
(11b-HSD1) catalyzes the interconversion of inactive
cortisone to the active steroid cortisol, which is the prin-
cipal circulating glucocorticoid in humans.1 This enzyme
is expressed in several tissues, such as liver, adipose, and
central nervous system.2 Excess glucocorticoids account
for increased glucose output in the liver, dampened glu-
cose-dependent insulin sensitivity in the adipose tissue,
and reduced insulin secretion from the pancreas. Due
to the close relationship between glucocorticoids and
metabolic disease risk factors, tissue specific 11b-
HSD1 inhibition has gained attention as a potentially
effective method for treating the metabolic syndrome,
including type 2 diabetes.3 This idea has been supported
by several model studies in animals. For example, 11b-
HSD1 knockout mice are resistant to diet induced obes-
ity and glucose intolerance,4 while transgenic mice that
overexpress 11b-HSD1 in adipose exhibit a phenotype
characterized by metabolic dysregulation, including
obesity, insulin resistance, glucose intolerance, and
hyperglycemia.5
A second isoform of this enzyme, 11b-HSD2, catalyzes
the reverse reaction, the conversion of cortisol to its
inactive keto form, cortisone. This enzyme is mainly ex-
pressed in kidney, gut, and placenta, where it acts to pre-
vent cortisol from stimulating the mineralocorticoid
receptor.6 It is thus important that inhibitors of 11b-
HSD1 do not significantly inhibit 11b-HSD2 in order
to avoid undesirable sodium retention, hypokalemia,
and hypertension.
Following the publication of arylsulfonamidothiazole
11b-HSD1 inhibitors,7 several other series have ap-
peared in the literature. 8 Herein we describe the synthe-
sis and SAR of pyridine amides as potent and selective
11b-HSD1 inhibitors, using a homogeneous Scintilla-
tion Proximity Assay (SPA) for in vitro screening in a
high-throughput 96-well plate format.9
Keywords: 11b-Hydroxysteroid dehydrogenase type 1; 11b-HSD1;
Pyridine amide.
Benzamide 1 (Fig. 1, human 11b-HSD1 IC50 = 235 nM)
was first identified through directed screening of our
*
Corresponding authors. Tel.: +1 609 818 6918 (H.W.); e-mail
addresses: haixia.wang@bms.com; zheming.ruan@bms.com
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.04.069

H. Wang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3168–3172
3169
acid, a modified literature procedure, which does not af-
fect the nitrogen of the pyridine ring.10 The bisaryl
analogue 9 was prepared through Suzuki coupling of
2-chlorophenylboronic acid and bromopyridine deriva-
tive 3. The related regioisomers and analogues of com-
pounds 6–9 were prepared by analogous routes.
Cl
Cl
S
O
S
N
O
O
Cl
N
2
R1
O
1
Analogues 11–14, which feature a one-atom linker, were
accessed through 6-chloropicolinic amide 10, which was
reacted with sulfur, oxygen, or nitrogen nucleophiles un-
der microwave irradiation to form the biaryl thioether
11, ether 12, or aniline 13, respectively (Scheme 2).
The biaryl sulfone analogue 14 was prepared via oxida-
tion of thioether 11.
B
A
NR2R3
N
Target
compounds
O
Fig. 1. Evolutionary path from screening lead 1 to pyridine amides.
A systematic evaluation of arylsulfonylmethylpyridyl
amides incorporating the 6 possible positional isomers
8, 15–19 was undertaken (Table 1). Two of the four
‘V-shaped’ isomers (i.e., 2,6- and 3,5-di-substituted pyr-
idyl amides 8 and 15) exhibited the greatest potency,
while the two linear isomers 18 and 19 exhibited the
weakest in vitro potency in this set. This is consistent
with the SAR in a benzamide series, where the meta-
substituted regioisomers have greater potency than their
corresponding para-substituted analogues (unpublished
results).
internal compound collection. A quick survey of differ-
ent linkers between the two aryl groups and various reg-
ioisomeric arrangements of 1 resulted in identification of
sulfone 2 (IC50 = 13 nM), which exhibits an approxi-
mately 20-fold improvement in potency. To improve
biological potency and increase structural diversity, ana-
logues featuring pyridyl rings in place of the central phe-
nyl ring and various linkers (A–B) between the two aryl
groups were synthesized and evaluated.
The synthetic route to pyridine amide derivatives featur-
ing a two-atom arene linker begins with conversion of
the commercially available 6-bromopicolinic acid to
the corresponding amide 3 via the acid chloride (Scheme
1). Subsequent catalytic carbonylation followed by
NaBH4 reduction yielded the alcohol, which was reacted
with SOCl2 to form intermediate chloride 5. Alkylation
with either thiophenoxide or phenoxide gave the corre-
sponding thioether 6 or the ether analog 7, respectively.
The thioether 6 was then oxidized to the corresponding
sulfone 8 using in situ generated p-toluenesulfonic per-
The effects of different amide groups on 11b-HSD1
activity were evaluated using a series of 3,5-disubstituted
derivatives analogous to 15, one of the two best tem-
plates from the initial SAR study. The pyrrolidine amide
20 was a significantly weaker inhibitor, though increas-
ing the lipophilic bulk steadily improved potency (Table
2). The 9-membered ring analogue 23 is 800-fold more
potent than pyrrolidine amide 20. On the other hand,
incorporating polar groups greatly decreased activity.
Replacing the methyl group in 15 with a primary amide
moiety as in 25 results in 100-fold loss in potency. The
inhibitory effect of morpholine amide 26 is minimal.
O
O
Br
N
Br
N
a, b
OH
N
3
c
O
O
O
O
N
MeO2C
N
Cl
N
d, e
Cl
N
N
Cl
N
a
N
OH
N
5
4
10
Cl
O
f
b
X
Cl
X
Cl
N
h
O
O
N
N
N
N
11, X=S
12, X=O
13, X=NH
Cl
O
S
Cl
O
c
6, X = S
9
N
g
7, X = O
N
8, X = SO2
O
Scheme 1. Reagents and conditions: (a) SOCl2; (b) 4-methlylpiperi-
dine, rt, CH2Cl2, 2-step: 95%; (c) Pd(OAc)2, DPPP, DBU, CO, MeOH/
DMF, 85 °C, 91%; (d) NaBH4, EtOH, rt, 59%; (e) SOCl2, CH2Cl2, rt,
quantitative; (f) Cs2CO3, DMF, 60 °C, X@S, 2,6-dichlorobenzenethiol,
98%; X@O, 2,6-dichlorophenol, 90%; (g) 1-tosyl-1H-imidazole, H2O2,
NaOH, THF/MeOH/H2O, rt, 94%; (h) 2-chlorophenylboronic acid,
Pd(PPh3)4, Na2CO3, toluene/EtOH/H2O, 80 °C, 49%.
14
Scheme 2. Reagents and conditions: (a) 4-methyl piperidine, HOAT,
EDAC, DMAP, CH2Cl2, rt, 88%; (b) Cs2CO3, DMF, microwave,
200 °C, X@S, 2-chlorothiolphenol, 81%; X@O, 2-chlorophenol, 32%;
X@N, 2-chloroaniline, 12%; (c) 1-tosyl-1H-imidazole, H2O2, NaOH,
THF/MeOH/H2O, 0 °C–rt, 36%.

3170
H. Wang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3168–3172
Table 1. SAR on the central pyridine core—regioisomers
Table 2. Variation of amides
Cl
Cl
O
O
S
S
NR2
N
N
Cl
O
O
Cl
O
O
Me
N
a
IC50 (nM)
Compound
Core
Compound
NR2
IC50 (nM)
2140
N
N
20
N
8
35
22
21
22
23
24
15
25
26
21
11
N
N
7
15
16
17
18
19
8
106
N
2.5
N
9
319
N
N
220
22
N
N
N
N
2050
2130
Me
O
2350
>104
NH2
a IC50’s refer to biochemical human 11b-HSD1 assay data.
N
O
A study of the 11b-HSD1 inhibitory effects with respect
to linkers was conducted in the 2,6-disubstituted pyri-
dine manifold, which was another potent scaffold (Table
3). Thiomethyl ether 6 was 5-fold more potent than sul-
fonylmethyl analogue 8, while the corresponding ether
analogue 7 was slightly less active. Due to the relative
ease of synthesis and similar potencies, the subsequent
linker study focused on utilization of the 2-chlorophenyl
group instead of the 2,6-dichlorophenyl group. Ana-
logues with single heteroatom linkers (11–13) are only
modestly active, while the strongly electron withdrawing
sulfonyl linkage in 14 was detrimental to 11b-HSD1 po-
tency. The biaryl analogue (9) exhibited potency compa-
rable to the two-atom linked derivatives. Additional
analogues featuring this linkage were prepared and eval-
uated (Table 4).
Table 3. Variation of linkers
O
X
L
N
N
Me
Compound
L
X
IC50 (nM)
6
8
SCH2
SO2CH2
OCH2
S
2,6-di-Cl
26-di-Cl
2,6-di-Cl
2-Cl
7.2
35
7
79
11
12
13
14
9
218
282
381
4670
17
O
NH
2-Cl
2-Cl
SO2
bond
2-Cl
2-Cl
Consistent with previous observations, when 4-methyl-
piperidyl amide 9 was replaced with the more lipophilic
3,3-dimethylpiperidyl amide group (27), the potency in-
creased 5-fold. Modifications on the distal aryl group
yielded highly potent compounds, including several
para-substituted analogues such as compounds 28–29.
The 3,4-disubstituted compound 30 was the most potent
inhibitor in this series (IC50 = 0.1 nM). With a decahy-
droquinolinyl amide group, analogues bearing strongly
electron deficient moieties such as 2-NO2Ph (31) and
4-CF3Ph (32) as well as the bulky biphenyl group (33)
were prepared and tested. All these groups appeared
to be well tolerated, exhibiting IC50’s in the single digit
nanomolar range.
A crystal structure of a complex between 11b-HSD1 and
compound 30 was obtained (Fig. 2).11 The crystal struc-
ture shows that the amide carbonyl oxygen is within
hydrogen bonding distance to two active site residues,
Ser170 and Tyr183. Compound 30 also forms a number
of favorable hydrophobic interactions with the protein.
The dimethylpiperidyl moiety is buried deep in the bind-

H. Wang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3168–3172
Table 4. Variation of aryl and amide groups
3171
O
N
NR2
X
Compound
X
NR2
IC50 (nM)
17
9
2-Cl
N
Me
Me
Me
27
28
29
30
31
32
33
2-Cl
2.9
1.1
1.1
0.1
2.0
3.6
4.7
N
Me
Me
Me
Me
4-Cl
N
Fig. 2. Crystal structure of compound 30 complexed with human 11b-
HSD1 and cofactor NADP. For clarity, the NADP has been omitted
from this representation, and only a few of the surrounding residues
are included in the figure, although the entire surface in the vicinity is
included. Color-coding: carbon—gray (11b-HSD1); green (compound
30), nitrogen—blue, oxygen—red, and fluorine—cyan. Initial Fo–Fc
density contoured at 3r is shown in cyan. Hydrogen bonds are shown
as small magenta spheres. This crystal form contains four 11b-HSD1
monomers per asymmetric unit and in two of them the 3-fluoro-4-
methylphenyl group is flipped 180° relative to the orientation shown
here. This figure was created with PyMol.12
Me
4-OCF3
3-F,4-Me
2-NO2
4-CF3
2-Ph
N
Me
N
N
gle digit nanomolar IC50 range have been identified.
Among the various pyridyl regioisomers, 2,6- or 3,5-
disubstituted analogues exhibit the greatest potency. Be-
tween the central pyridyl and distal aryl groups, multiple
linkers appear well tolerated and lipophilic amide
groups are favored. The results from further studies will
be reported in due course.
N
N
Table 5. Potent inhibitors in the arylbenzyl ether amide chemotype
X
ing pocket, and interacts with the side chains of Thr124
and several other amino acid residues.11 The central pyr-
idyl core interacts with both the side chain and back-
bone of Tyr177. The 3-fluoro-4-methylphenyl moiety is
closest to the entrance to the pocket and it also interacts
with the side chain of Tyr177, albeit from a different
angle.
O
O
NR2
N
Compound
X
py Core NR2
IC50 (nM)
2.0
34
2,6-di-Cl
3,5
N
N
Novel 11b-HSD1 inhibitors with single digit nanomolar
IC50’s were identified in three distinct series: arylsulfo-
nylmethyl pyridyl amides (e.g., 23), arylthiomethyl pyr-
idyl amides (e.g., 6), and biaryl amides (e.g. 27–33).
However, further potency improvement was still desired
for another series of interest, the arylbenzyl ethers. Sev-
eral combinatorial libraries featuring ether linkages were
prepared and tested, and some selected compounds from
these efforts are listed in Table 5. Modifications on the
aryl and amide groups led to a variety of active com-
pounds featuring both 3,5- and 2,6-disubstituted pyri-
dine analogues (34–37).
H
Me
N
35
2,6-di-Cl
3,5
1.7
Me
Me
N
36
37
2,4,6-tri-Cl 2,6
6.5
4.6
Me
Me
2,6-di-Cl
2,6
Through an extensive SAR study on various regions of
the pyridine amide structure, a series of potent and selec-
tive 11b-HSD1 inhibitors that exhibit potency in the sin-
N

3172
H. Wang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3168–3172
Patel, J. R.; Shuai, Q.; Dinges, J.; Winn, M.; Pliushchev,
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over-expressing human 11b-HSD1 were incubated with
the substrate cortisone and cofactor NADPH at room
temperature. The reactions were terminated with the
addition of a nonspecific 11b-HSD1 inhibitor (18b-glyc-
yrrhetinic acid). The product cortisol was quantified in an
immuno-competition SPA wherein the [3H]-cortisol bound
to anti-rabbit antibody Yitrium silicate SPA beads coated
with polyclonal anti-cortisol antibody was competed by
cortisol produced in the reaction, and the reaction mixture
was read in a scintillation plate reader (TopCount). The
amount of cortisol was determined from a cortisol
standard curve; (b) To ensure that compounds were
selective for 11b-HSD1 versus 11b-HSD2, all active
inhibitors of interest (11b-HSD1 IC50 < 100 nM) were
counter-screened in an in vitro 11b-HSD2 assay. Human
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the compounds in this series showed significant inhibition
of 11b-HSD2 at 10 lM.
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11. PDB Deposition number is 3CH6. The dimethylpiperid-
inyl moiety also interacts with the side chains of Ile121,
Tyr183, Val227, and the nicotinamide moiety of NADP.
The central pyridinyl moiety interacts with Tyr177 side
chain and the main chain in the vicinity of Gly216 and
Leu217. Besides Tyr177, the 3-fluoro-4-methylphenyl
moiety interacts with the side chains of Leu126, Met179,
Val231, and Tyr284 from the other chain of the 11b-HSD1
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