Optimization of 1,2,4-triazolopyridines as inhibitors of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1)

Article abstract of DOI:10.1021/ml500144h

Small alkyl groups and spirocyclic-aromatic rings directly attached to the left side and right side of the 1,2,4-triazolopyridines (TZP), respectively, were found to be potent and selective inhibitors of human 11β- hydroxysteroid dehydrogenase-type 1 (11β-HSD-1) enzyme. 3-(1-(4-Chlorophenyl)cyclopropyl)-8-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine (9f) was identified as a potent inhibitor of the 11β-HSD-1 enzyme with reduced Pregnane-X receptor (PXR) transactivation activity. The binding orientation of this TZP series was revealed by X-ray crystallography structure studies.

Full text of DOI:10.1021/ml500144h

Letter
pubs.acs.org/acsmedchemlett
Optimization of 1,2,4-Triazolopyridines as Inhibitors of Human 11β-
Hydroxysteroid Dehydrogenase Type 1 (11β-HSD-1)
Jun Li,*,† Lawrence J. Kennedy,† Haixia Wang,† James J. Li,† Steven J. Walker,† Zhenqiu Hong,†
Stephen P. O’Connor,† Akbar Nayeem,∥ Daniel M. Camac,# Paul E. Morin,# Steven Sheriff,#
Mengmeng Wang,⊥ Timothy Harper,⊥ Rajasree Golla,§ Ramakrishna Seethala,§ Thomas Harrity,‡
Randolph P. Ponticiello,‡ Nathan N. Morgan,‡ Joseph R. Taylor,‡ Rachel Zebo,‡ David A. Gordon,‡
and Jeffrey A. Robl*,†
‡
§
∥
⊥
†Department of Medicinal Chemistry, Department of Biology, Lead Evaluation, CADD, Department of Pharmaceutical
Candidate Optimization, Bristol-Myers Squibb, Bldg 13, Princeton, New Jersey 08543-5400, United States
#Protein Science & Structure, Research & Development, Bristol-Myers Squibb, Princeton, New Jersey 08543, United States
S
* Supporting Information
ABSTRACT: Small alkyl groups and spirocyclic-aromatic rings directly
attached to the left side and right side of the 1,2,4-triazolopyridines (TZP),
respectively, were found to be potent and selective inhibitors of human 11β-
hydroxysteroid dehydrogenase-type 1 (11β-HSD-1) enzyme. 3-(1-(4-
Chlorophenyl)cyclopropyl)-8-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine
(9f) was identified as a potent inhibitor of the 11β-HSD-1 enzyme with
reduced Pregnane-X receptor (PXR) transactivation activity. The binding
orientation of this TZP series was revealed by X-ray crystallography structure studies.
KEYWORDS: Enzyme inhibitors, human 11β-hydroxysteroid dehydrogenase-type 1, triazolopyridines
lucocorticoids such as cortisol are stress hormones that
play an important role in regulating carbohydrate,
reported as a potential treatment for diabetes, metabolic
syndrome, and related disorders.12−21
G
protein, and lipid metabolism, as well as modulating
inflammatory and immune responses. Glucocorticoids are
present in two forms in humans: the active cortisol (cortico-
sterone in rodents) and the inactive cortisone (11-dehydro-
corticosterone in rodents). Excess cortisol expression in
humans, as typified in patients with Cushing’s syndrome, can
cause a variety of abnormalities including obesity, insulin
resistance, hyperglycemia, dyslipidemia, and hypertension.
These symptoms are also typically found in patients with
Our laboratory has recently reported novel inhibitors of 11β-
HSD-1 based on a 1,2,4-triazolopyridine (TZP) framework,
represented by compound 1 (Figure 1), which showed
reasonable good potency but with liabilities, such as PXR
activity (EC50 = 1.2 μM). Structure−activity relationship (SAR)
optimization of substituents at the C-3 and C-8 positions of the
TZP core resulted in the identification of compound 2a as a
reasonable potent and metabolically stable inhibitor of the
metabolic syndrome or related diabetes/obesity diseases.1−3
A
good correlation of salivary cortisol levels with components of
the metabolic syndrome have been reported.4 Largely expressed
in liver and adipose tissue, 11β-HSD-1 is an enzyme that
catalyzes the conversion of inactive cortisone to the active
glucocorticoid hormone cortisol.5 Transgenic mice that over-
express 11β-HSD-1 in the adipose develop many of the features
of metabolic syndrome, including glucose intolerance, insulin
resistance, dyslipidemia, hypertension, and obesity.6,7 In
contrast, whole-body genetic knockout of 11β-HSD-1
expression in mice placed on a high fat diet has been shown
to improve glucose tolerance and reduce triglyceride level
relative to wild-type controls on a similar diet.8 These
preclinical results suggest that inhibition of 11β-HSD-1 activity
in humans may provide a beneficial impact for the treatment of
metabolic syndrome. As a result, significant attention has been
given to modulation of this enzyme from both academia and
industry,9−11 and numerous selective inhibitors have been
Figure 1. Generation of lead 1,2,4-trizolopyridine (TZP) 11β-HSD-1
inhibitor 3b based on previous leads 1 and 2a.
Received: April 9, 2014
Accepted: May 22, 2014
© XXXX American Chemical Society
A
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ACS Medicinal Chemistry Letters
Letter
enzyme without Pregnane-X receptor (PXR) activity.22 While
certain aliphatic bicyclic rings (such as the bicyclo[2.2.2]octan-
1-ol in compound 2a) served well to address potency and
metabolic stability issues for this chemotype, the rigidity and
limited synthetic accessibility of these bridged structures made
further modification to this moiety very challenging. Looking to
incorporate simpler replacements for the bicyclic ring system,
we turned our attention to incorporation of a 3-(1-phenyl)-
cyclopropyl functionality, which was previously identified as a
potent binding pharmacophore in a related series of substituted
triazoles.15,23 Indeed, replacement of the bicyclo[2.2.2]octan-1-
ol moiety in 2a with 4-chlorophenyl-cyclopropyl group resulted
in 3b, a compound that possessed excellent inhibitory activity
toward human 11β-HSD-1 (IC50 = 1.0 nM) while retaining
good metabolic stability. Unfortunately the modification also
resulted in a significantly increased liability for PXR trans-
activation, an off-target liability that was also observed in a
series of related triazoles from Merck.15,16 As such we initiated
a systematic SAR study to determine if a robust separation of
PXR transactivation from dehydrogenase activity was possible
in this series.
Table 1. SAR of 3-[1-(4-Chlorophenyl)cyclopropyl]-8-
aryloxy-TZP Analogues 3a−3l
a
a
compd
aryl
IC50 (nM) PXR EC50 (μM)/Ymax (%)
3a
3b
3c
3d
3e
3f
Ph
1.7
1.0
22
1.8/71
0.97/100
0.8/95
1.2/85
1.1/86
0.4/123
0.3/123
2.6/50
0.7/105
0.5/95
0.8/75
2.8/63
2-Cl-Ph
3-Cl-Ph
4-Cl-Ph
2-F-Ph
21
0.7
0.9
0.5
1.4
8.1
2.7
20
2-(N-morpholinyl)-Ph
2-CF3O-Ph
3g
3h
3i
2-hydroxyl-Ph
2-methylsulfonyl-Ph
2-Ph-Ph
3j
3k
3l
2-naphthyl
2-Me-pyridin-3-yl
5.5
a
Our initial SAR approach focused on modification of the left-
hand portion of the molecule. A convenient synthesis of these
derivatives is given in Scheme 1. The commercially available 1-
IC50 values refer to biochemical human 11β-HSD-1 assay data;
average of at least two replicates.
similar human 11β-HSD-1 inhibition potencies. The more
polar hydroxyl group (3h) was also well tolerated, but the
methylsulfonyl group (3i) exhibited attenuated in vitro activity.
A phenyl (3j) at the ortho-position exhibited good potency, but
fused 2-naphthalene analogue (3k) was much less active. While
the majority of these analogues showed high human 11β-HSD-
1 inhibitory activity, all possessed significant PXR activity (EC50
< 3 μM). The more lipophilic analogues (e.g., 3g and 3f) were
among the most potent tranasactivators in this series.
Incorporation of polar groups (e.g., 3h and 3l) only had a
modest effect on attenuating PXR transactivation.
a
Scheme 1
We next directed our attention to the incorporation of
smaller aliphatic rings at the C-8 position of the TZP core.
Introduction of cycloalkyl substituents was achieved via
reaction of bromo-TZP intermediate 7 with various alkyl
boronic acids or alkyl zinc halides under Pd-catalysis (Scheme
2). This method was used to generate compounds 9e−g in 40−
75% yields. Compound 9h was made directly from 2-
hydrazinyl-3-methylpyridine as shown in Scheme 1.
a
Reagents and conditions: (a) N-methylmorpholine, i-BuOCOCl, 0
°C, (90%); (b) PPh3Cl2, N,N-diisopropylethylamine, CH2Cl2, rt,
(75%); (c) Cs2CO3, DMF or neat, 120 °C.
(4-chlorophenyl) cyclopropane-1-carboxylic acid (4) was
coupled with hydrazine 5 to afford acyl hydrazide 6 in good
yield (90%). Mild cyclodehydration of 6 using PPh3Cl2
produced bromo-triazolopyridine 7 in 75% yield. Coupling of
7 with various phenols 8 under modified literature conditions
(i.e., Cs2CO3 under concentrated or neat reaction conditions)
typically resulted in acceptable yields (>50%) of final products.
Analogues 3a−l were synthesized via this route as well as
analogues 9a−d with lower yield (5−20%).
a
Scheme 2. Synthesis of Alkyl-TZP Analogues
As outlined in Table 1, the presence of the ortho-Cl
substituent 3b only marginally enhanced potency as compared
to the unsubstituted phenyl analogue 3a. A chlorine was
employed to study the positional effect of phenyl substitution.
Compared with ortho-substituted phenyl analogue 3b, chlorine
at the meta- and para-positions of the phenyl ring (3c and 3d,
respectively) resulted in a significant loss of potency. This
finding suggested that the ortho-position may be a favorable
site to explore additional substituent effects on the phenyl ring.
For this purpose, several functional groups with varied steric
and electronic properties were introduced. Groups such as
fluoro (3e), an electron-donating N-morpholinyl (3f), and the
large hydrophobic trifluoromethoxy (3g, ClogP, 6.07) afforded
a
Reagents and conditions: alkyl-B(OH)2 or alkyl-Zn-Br, 1,1′-bis-
(diphenylphosphino)ferrocene palladium(II)dichloride dichlorome-
thane complex, K3PO4 or K2CO3, 85 °C, DMF.
Among the first analogues examined (Table 2) was the
cyclohexyloxy derivative 9a, which was the aliphatic counterpart
of compound 3a. However, compound 9a showed much
weaker 11β-HSD-1 inhibition while retaining similar PXR
activity. Attenuated potency was also observed for the
cyclopropylmethoxy analogue 9c. Although the 4-tetrahydro-
pyranyloxy substituent 9b (ClogP, 3.49) exhibited reduced 11β-
B
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ACS Medicinal Chemistry Letters
Letter
triazole core and is the most closely resembled TZP core of
interest (PDB code 3D5Q).24,25 While complete flexibility of
the ligands was assumed in the calculation, the receptor was
treated rigidly during docking, and the docking site was
assumed to be the pocket occupied by the ligand in the 11β-
HSD-1 complex. As a post processing step, local energy
minimization in the gas phase using the OPLS 2005 force field
was carried out in order to relax the overall structure; this also
allowed for partial flexibility of the receptor atoms surrounding
the docked ligand. The favored poses from the docking
calculations are shown in Figure 3 along with the residues in
Table 2. SAR of 3-[1-(4-Chlorophenyl)cyclopropyl]-TZP
9a−h with (Cyclo)alkyloxy and Cycloalkyloxy or Alkyl
a
Groups at C-8
a
compd
R
IC50 (nM) PXR EC50 (μM)/Ymax (%)
9a
9b
9c
9d
9e
9f
cyclohexyloxy
4-tetrahydropyranyloxy
c-PrCH2O
42
0.6/103
10/52
65
51
not tested
1.5/60
0.9/24
50/14
cyclobutoxy
cyclobutyl
4.2
2.4
1.6
0.61
17
cyclopropyl
isopropyl
9g
9h
1.0/34
8.8/22
methyl
a
IC50 values refer to biochemical human 11β-HSD-1 assay data;
average of at least two replicates.
HSD-1 inhibitory potency, the dramatically reduced PXR
activation profile (EC50 = 10 μM, Ymax = 52%) again suggested
that reducing lipophilicity at this position of the molecule was
desired. A significant advance was observed by removing “O”
linker affording compounds 9e−9h, which exhibited good to
excellent 11β-HSD-1 potency while attenuating the full agonist
profile (Ymax < 35%) for PXR. The “sweet-spot” in this SAR
study is observed with compound 9f, which exhibits a superior
combination of high enzyme inhibitory activity and low PXR
transactivation (EC50 > 50 μM).
Certain structure−activity and structure−liability relation-
ships observed in this new TZP series (as exemplified by
compounds 9b and 9f) appeared highly reminiscent with that
observed in the lead TZP chemotype (as exemplified by
compound 2a). The original assumption that the 1-(4-
chlorophenyl)cyclopropyl group in 3b was a surrogate for the
[2,2,2]-bicyclooctanol group in 2a may now be better explained
by an ∼180° rotation of the TZP core so that the 1-(4-
chlorophenyl)cyclopropyl group in 3b (now spatially repre-
sented by 3b′) is actually substituting for the 3-chloro-2-
methylphenoxy group in 2 instead (see Figure 2).
Figure 3. Preferred binding poses of compounds 2a and 3b using
protein coordinates from 3D5Q, which has a 1,2,4-triazole ligand
bound at the active site. The protein carbon atoms are shown in green
and those of compound 2a and 3b in cyan; nitrogen atoms are shown
in blue, oxygen atoms in red, and chlorine atoms in dark green. The
interatomic distances (in Angstroms) between polar ligand atoms and
protein residues that are indicative of hydrogen bonds are shown in
magenta.
the binding pocket that contribute most significantly to the
binding energy. The most striking observation is that the two
compounds 2a and 3b bind to 11β-HSD-1 in opposite
orientations, as inferred from our SAR studies. As with the
triazole structure 3D5Q, both TZPs bind in an orientation in
which the triazole ring is oriented toward the side chains of
Ser170 and Tyr183 suggesting probable hydrogen bonds. The
overall docking pose shows that the phenoxy substituent at the
8 position in the TZP scaffold lies on opposite sides of the
binding pocket in compounds 2a and 3b. As seen in Figure 3A,
the preferred tendency of 2a to bind in an orientation opposite
to 3b may be caused by the tendency of the hydroxyl group on
the bicyclo[2.2.2]octyl ring in the former to form a hydrogen
bond with the backbone carbonyl oxygen on Thr124. The
interaction energy of this hydrogen bond is estimated at about
1.5 kcal/mol from the docking result, favoring this pose over
the 180-degree flipped pose (as for compound 3b).
The opposite binding orientations based on docking suggests
that while analogues of compound 2a (lead TZP series) will
bind in the orientation shown for 2a, analogues of compound
3b (alternate TZP series), which besides the two hydrogen
bond interactions shown in Figure 3B does not show any other
polar interactions between ligand and protein, may often bind
in an orientation similar to 2a rather than 3b depending on the
nature of the substitutions in the two terminal phenyl rings.
This is consistent with the observation that the SAR for C-3
and C-8 substitutions on the TZP core do not parallel for the
lead and alternate series.
The observed SAR findings and docking calculation
predictions prompted us to further examine the binding
mode of these compounds to 11β-HSD-1 using X-ray
crystallography to confirm the binding orientation. Although
X-ray crystal structures are not available for a human 11β-HSD-
Figure 2. Reversal of core binding orientations for “original” TZP
series 2a versus “alternate” TZP series 9b.
In order to visualize binding modes for compounds in the
two TZP subseries, compounds 2a and 3b were docked into a
crystal structure of 11β-HSD-1 complexed with NADPH and a
ligand, 3-[1-(4-fluorophenyl)cyclopropyl]-4-(1-methylethyl)-
5-[4-(trifluoromethoxy)phenyl]-4H-1,2,4-triazole (structure
shown in Supporting Information), which contains a 1,2,4
C
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ACS Medicinal Chemistry Letters
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1 complex with either compound 2a or 3b, the complex
structures of closely related analogues 2b and 3e (Figure 4)
superposition of compounds 2b and 9f and surrounding
residues are shown in Figure 5D. These findings are consistent
with previously reported ∼180° flips of inhibitors of 11β-HSD-
1 derived from different chemical series by others,28 and further
revealed the flexibility of 11β-HSD-1 inhibitor of binding mode.
As compound 9f seemed to afford a superior combination of
potency, low PXR activity, and reasonable solubility (76 μg/
mL, pH 7.4), it was selected for more extensive in vitro and in
vivo evaluation. As observed with other analogues in this series,
compound 9f was essentially inactive versus 11β-HSD-2 (IC50
> 10 μM), an unwanted activity. With the exception of
CYP2C19 (IC50 ≈ 2 μM), compound 9f was not a significant
inhibitor of other human CYP450 enzymes such as 1A2, 2C8,
2C9, 2D6, or 3A4 (IC50 > 20 μM). Ion channel activities
including hERG were acceptable (hERG flux IC50 > 60 μM).
Excellent in vitro metabolic stability in isolated microsomes was
observed across all species tested (human, mouse, cyno, and
rat: ∼100% remaining after 30 min of incubation). When orally
dosed to male Balb/C mice at 3.5 mpk (0.5% methocel/0.1%
Tween-80 in water as the vehicle), oral absorption was rapid
with a short tmax (1 h). The maximum plasma concentration
cmax was 2.5 μM, and plasma exposure was acceptable with the
AUC (0−8 h) reaching 5.6 μM·h. The compound was found to
distribute extensively in adipose tissue as well, affording an
adipose/plasma ratio of ∼5 when measured 8 h postdosing.
Although compound 9f demonstrated excellent human 11β-
HSD-1 inhibition (IC50 = 1.6 nM), its activity was dramatically
weaker for the murine enzyme (IC50 = 241 nM). A significant
difference in potency with respect to species was also observed
comparing activities in human (HEK IC50 = 13 nM) and mouse
(3T3L1 IC50 = 293 nM) derived cellular assays. Indeed,
attenuated activity for mouse and rat (versus human or cyno)
11β-HSD-1 was typically consistent across the chemotype and
complicated in vivo testing of analogues with this series. As
such, it was not surprising that compound 9f failed to elicit a
response in a standard DHC challenge assay in mice at doses
up to 30 mpk.
In summary, a series of novel, potent, and selective inhibitors
of human 11β-HSD-1 enzyme were revealed through
structure−activity relationship studies of a 1,2,4-triazolopyr-
idine (TZP) core, and representative lead compounds such as
9f were identified. A disconnect in the SAR between analogues
in this series (represented by compounds like 3e and 9f) and
the lead TZP analogue 2a suggested a “flipped” binding
orientation within the catalytic site of 11β-HSD-1, which was
confirmed by docking calculations and X-ray structure studies.
This finding suggests that the TZP core might provide an ideal,
flexible platform for future compound optimization. While
these compounds proved to be challenging to evaluate due to
their weak rodent activities, they served as excellent starting
points for further modifications of this chemotype resulting
from discovery of our clinical candidate, which will be reported
in due course.
Figure 4. Structures and human 11β-HSD-1 activities of compounds
2b and 3e.
Figure 5. Binding of compounds to human 11β-HSD-1 as obtained
through X-ray crystallographic analysis. Figures 5A (2b), B (3e), and
C (9f) show the final coordinates with the initial (prior to placement)
2Fo − Fc electron density (magenta; contoured at 1 rmsd) and several
surrounding residues. Carbon atoms of compounds are shown in green
and those of 11β-HSD-1 in cyan. Nitrogen atoms are shown in blue,
oxygen atoms in red, fluorine atoms in teal, and chlorine atoms in pea
green. Hydrogen bonds are shown as a series of ellipsoids (black). In
particular, note that the two exposed nitrogen atoms of the triazolyl
moiety form hydrogen bonds to Ser 170 OH and Tyr 183 OH. Figure
5D depicts the superposition of compounds 2b (cyan) and 9f
(magenta) and surrounding residues showing that the orientation of
the core triazolopyridine flips ∼180° about the vertical axis while
maintaining the hydrogen bonds to Ser 170 OH and Tyr 183 OH.
Note also that the o-fluorophenyl moiety of compound 2b forces Tyr
177 side chain to flip out of the way.
were obtained at 2.35 Å resolution (Figure 5).26,27 The X-ray
crystal structures confirmed our hypothesis: the orientation of
the core TZP rings are indeed rotated ∼180° about the vertical
axis for the two compounds as shown in Figure 2 while
maintaining productive hydrogen bonding interactions to the
Ser 170 and Tyr 183 hydroxyl groups (compare Figure 5A,B).
Furthermore, compound 9f was also shown to exhibit the same
orientation as that of 3e (Figure 5C). It is worthy to point out
that the phenylcyclopropyl group in the 3D5Q ligand is
oriented toward T124, whereas in 3e and 9f it is oriented in the
opposite direction, toward Y177, as determined by the
preferred binding orientation. For direct comparison, the
ASSOCIATED CONTENT
■
S
* Supporting Information
Protocols or methods of in vitro and in vivo assays, analytical
and spectroscopic data for compounds 3−9h, and X-ray
crystallographic data of compound 2b, 3e, and 9f. This material
is available free of charge via the Internet at http://pubs.acs.org.
D
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ACS Medicinal Chemistry Letters
Letter
dehydrogenase type 1: Discovery of PF-915275. Bioorg. Med. Chem.
Lett. 2009, 19, 3493−3497.
AUTHOR INFORMATION
Corresponding Authors
*(J.L.) Tel: 609-818-7123. E-mail: jun.li@bms.com.
*(J.A.R.) Tel: 609-818-5048. E-mail: jeffrey.robl@bms.com.
Notes
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Huber, R. The 11β-hydroxysteroid dehydrogenase type 1 inhibitor
INCB13739 improves hyperglycemia in patients with type 2 diabetes
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The authors declare no competing financial interest.
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ABBREVIATIONS USED
■
11β-HSD-1, 11β-hydroxysteroid dehydrogenase type 1; TZP,
triazolopyridines; PXR, Pregnane-X receptor
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F
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