Discovery of Clinical Candidate BMS-823778 as an Inhibitor of Human 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD-1)

Article abstract of DOI:10.1021/acsmedchemlett.8b00307

BMS-823778 (2), a 1,2,4-triazolopyridinyl-methanol derived analog, was identified as a potent and selective inhibitor of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) enzyme (IC₅₀ = 2.3 nM) with >10,000-fold selectivity over 11β-HSD-2. Compound 2 exhibits robust acute pharmacodynamic effects in cynomolgus monkeys (ED₅₀ = 0.6 mg/kg) and in diet-induced obese (DIO) mice (ED₅₀ = 34 mg/kg). Compound 2 also showed excellent inhibition in an ex vivo adipose DIO mouse model (ED₅₀ = 5.2 mg/kg). Oral bioavailability ranges from 44% to 100% in preclinical species. Its favorable development properties, pharmacokinetics, high adipose-to-plasma concentration ratio, and preclinical pharmacology profile have prompted the evaluation of 2 for the treatment of type 2 diabetes and metabolic syndrome in phase 2 clinical trials.

Full text of DOI:10.1021/acsmedchemlett.8b00307

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Letter
Discovery of Clinical Candidate BMS-823778 as an Inhibitor of
Human 11#-Hydroxysteroid Dehydrogenase Type 1 (11#-HSD-1)
Jun Li, Lawrence J. Kennedy, Steven J Walker, Haixia Wang, James J Li, Zhenqiu Hong, Stephen P
O'Connor, Xiang-Yang Ye, Stephanie Y Chen, Shung Wu, David S Yoon, Akbar Nayeem, Daniel M
Camac, Vidhyashankar Ramamurthy, Paul E Morin, Steven Sheriff, Mengmeng Wang, Timothy M. Harper,
Rajasree Golla, Ramakrishna Seethala, Thomas W Harrity, Randolph P. Ponticiello, Nathan N. Morgan,
Joseph R. Taylor, Rachel Zebo, Brad D. Maxwell, Frederick Moulin, David A. Gordon, and Jeffrey A Robl
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.8b00307 • Publication Date (Web): 13 Nov 2018
Downloaded from http://pubs.acs.org on November 14, 2018
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Discovery of Clinical Candidate BMS-823778 as an Inhibitor of Hu-
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man 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD-1)
Jun Li*a, Lawrence J. Kennedya, Steven J. Walkera, Haixia Wanga, James J. Lia, Zhenqiu Honga, Stephen
P. O'Connora, Xiang-yang Yea, Stephanie Chena, Shung Wua, David S. Yoona, Akbar Nayeemb, Daniel
M. Camacb, Vidhyashankar Ramamurthyb, Paul E. Morinb, Steven Sheriffb, Mengmeng Wanga, Timothy
W. Harpera, Rajasree Gollaa, Ramakrishna Seethalaa, Thomas Harritya, Randolph P. Ponticielloa, Nathan
N. Morgana, Joseph R. Taylora, Rachel Zeboa, Brad Maxwellb, Frederick Moulina, David A. Gordona,
Jeffrey A. Robla
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a
Research & Development, Bristol-Myers Squibb, P.O. Box 5400, Princeton, NJ 08543
b
Research & Development, Bristol-Myers Squibb, P.O. Box 4000, Princeton, NJ 08543
ABSTRACT: BMS-823778 (2), a 1, 2, 4-triazolopyridinyl-methanol derived analog was identified as a potent and selective inhibitor
of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) enzyme (IC50 = 2.3 nM) with > 10,000-fold selectivity over 11-
HSD-2. Compound 2 exhibits robust acute pharmacodynamic effects in cynomolgus monkeys (ED50= 0.6mg/kg) and in diet-induced
obese (DIO) mice (ED50= 34mg/kg). 2 also showed excellent inhibition in an ex vivo adipose DIO mouse model (ED50 = 5.2 mg/kg).
Oral bioavailability ranges from 44% to 100% in preclinical species. Its favorable development properties, pharmacokinetics, high
adipose-to-plasma concentration ratio and pre-clinical pharmacology profile have prompted the evaluation of 2 for the treatment of
type 2 diabetes and metabolic syndrome in phase 2 clinical trials.
KEYWORDS: Enzyme inhibitors, human 11β-hydroxysteroid dehydrogenase-type 1, 11-HSD-1, trizolopyridine, 1, 2, 4-tria-
zolopyridinyl-methanol, BMS-823778, high adipose selectivity, type 2 diabetes, cortisol, cortisone
Diabetes continues to be a worldwide epidemic disease. A
WHO report issued in 2015 showed that globally 8.5 % of
adults had diabetes in 2014 with type 2 diabetes making up
about 90% of the cases, and the death of people caused by dia-
betes rose to 1.5 million in 2012.1 Type 2 diabetes is a long-
term metabolic disorder, typically associate with high blood
sugar, insulin deficiency in some cases, and insulin resistance.
While several existing options for diabetic treatment are avail-
able, current clinical evidence advocates that a better control of
blood sugar level is desired and combination therapy is usually
more effective in achieving the target glycemic level, thereby
discovery and development of new diabetic drugs with novel
mechanisms of action to medically manage type 2 diabetes are
greatly needed.
11-HSD-1 activity in humans may help the treatment of met-
abolic syndrome and diabetes.5 As a result, significant efforts to
discover inhibitors of 11β-HSD-1 have been reported.8-15
We have previously reported a novel inhibitor of 11β-HSD-1
compound 1 (Figure 1), which was derived from a 1, 2, 4-tria-
zolopyridine (TZP) core structure.13 Compound 1 showed ex-
cellent human11β-HSD-1 enzyme inhibitory activity (IC50 =1.6
nM) and low Pregnane-X receptor (PXR) transactivation
(EC50> 50 μM), a major off-target liability for this class of com-
pounds. However, the murine enzyme activity of 1 was much
weaker (m-11-HSD-1 IC50 =241 nM). 1 also demonstrated
limited aqueous solubility (219 g/ml at pH7) which made high
dose in vivo evaluation difficult. In addition, a potential Cyto-
chromes P450 (CYP) inhibition liability (2C19 IC50 = 1.9 )
was present which may raise potential drug-drug interaction is-
sues in clinical development. Ultimately, the failure to prompt
a robust response in vivo in a standard11-dehydrocorticosterone
(DHC) challenging assay in mice made it difficult to further
evaluate the potential of 1. Thus, a better and more optimized
compound was sought.
The active glucocorticoid, cortisol, in human regulates a wide
range of processes throughout the body, including metabolism,
inflammatory and immune response. High salivary cortisol lev-
els was found to be associated with components of metabolic
syndrome andglucose level, 2 thus a potential therapeutic treat-
ment for metabolic syndrome and diabetes can be realized
through regulating or reducing the cortisol level in the human
body. 11β-Hydroxysteroiddehydrogenase type 1 (11β-HSD-1),
an enzyme mainly expressed in liver and adipose tissue, con-
verts inactive cortisone to the active cortisol.3 Numerous pre-
clinical studies regarding the role of 11β-HSD-1 have been re-
ported.4-8 These preclinical results suggested that inhibition of
Compound 1 proved to be an excellent starting point for modi-
fications of this chemotype due to its excellent activity with
minimal PXR liability. We decided to concentrate on variations
of the small alkyl group on the left side of the molecule, a
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“sweet-spot” for SAR changes, where it was shown that varia-
1, in this case corticosterone, was measured by immunoassay.
Inhibition of 11β-HSD-1 was observed as a measure of decrease
in the plasma concentration of corticosterone. Drug plasma con-
centrations were measured concurrently. The ED50 value of 2
was found to be 34 mg/kg in mice and 0.6 mg/kg in cynomolgus
monkeys. The difference between the ED50 values for these two
species (~57 fold) is consistent with the difference of their in-
trinsic potencies (~55-fold based on Ki value).
1
2
3
4
5
6
7
8
tion at this position can maintain the potency with the benefit of
attenuation of PXR activity.13 With this focus in mind, we
sought to further improve ADME profiles such as solubility and
CYP inhibition by incorporating polar functionalities with a pri-
mary focus on hydroxyl groups. Simply replacing the cyclopro-
pyl group with a hydroxymethyl group (3a) resulted in a ~10-
fold loss of potency. Two hydroxyl groups (3b) further de-
creased potency indicating that a balance of polarity is needed
at this position. Thus, reinstallation of small hydrophobic alkyl
groups was explored. Adding a cyclopropyl group to 3a, which
resulted in 3c, improved human 11β-HSD-1 inhibitory potency
but further reduced activity versus the mouse enzyme. On the
other hand, attempting to increase alkyl chain length by insert-
ing an ethyl group between the TZP core and the hydroxylme-
thyl group (3d) only slightly improved the potency over 3a.
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Table 1. SAR Results of 3-[1-(4-chlorophenyl)cyclopropyl]-8-ar-
yloxy-TZP analogs 3a-3d and 2
Compd
R
h-
IC50
(nM)
m-
IC50
(nM)
PXR
EC50
(M)
cLogP


3a
3b
17
3800
25
2.7
1.3
71
>10000
>50
Figure 1. Lead compound 1
Adding more lipophilicity (3e) by introduction of a terminal
gem-dimethyl group on 3d was found to diminish potency and
increase the unwanted PXR activity. Moving the gem-dimethyl
group to the benzylic position (3f) significantly increased the
potency but enhanced the PXR liability. Optimally it was found
that reducing the chain length of 3f, resulting in 2, afforded a
compound with potent human 11-HSD-1 inhibition (IC50 = 2.3
nM), remarkable aqueous solubility (Table 5, supporting infor-
mation), and negligible PXR activity, although mouse 11-
HSD-1 inhibition (IC50 = 600 nM) was still moderate. Interest-
ingly, although cLogP generally correlated with human 11-
HSD-1 potency within the triazolopyridinyl-methanol chemo-
type, it didn’t show a similar trend for PXR activity. Other polar
functionalities such as a carboxylic acid group (3g) were also
explored, which resulted in a significant loss of potency (Table
1).
3c
5.9
8060
5700
48
25
3.0
2.8
3d
11
3e
3f
2
43
0.5
2.3
>10000
1150
600
3.6
1.3
3.5
3.6
2.3
>50
3g
1280
>10000
>50
3.2
A full enzyme kinetic analysis of the microsomal form of hu-
man 11β-HSD-1 at the biologically relevant temperature of 37
°C was performed on 2 and yielded a Ki value of 0.9 nM (Table
2, supporting information). The Ki values for the cynomolgus
monkey and mouse enzymes were 7 nM and 380 nM, respec-
tively. In addition, no 11β-HSD-2 inhibition up to 30 μM versus
the human enzyme and up to 20 μM versus the corresponding
mouse, rat and monkey enzymes were found for 2.
IC50 and PXR values refer to average of at least two duplicates
cLogP calculated by Chemdraw professional, version 16.0.1.4, Perkin
Elmer Informatics, Inc
While the pharmacodynamic models described above are useful
for assessing the activity of compounds in an intact animal, it
did not allow for a discrete assessment of drug activity in spe-
cific tissues of interest. Adipose is believed to be a key target
organ for inhibitors of 11β-HSD-1.4,16 Thus a DIO mouse based
ex vivo model was used to further evaluate 2. Male DIO mice
were treated with various doses of 2 via oral gavage. Three
hours later, the animals were sacrificed, the adipose tissue was
Inhibition of 11β-HSD-1 in vivo was accomplished using a
pharmacodynamic (PD) protocol in mice and cynomolgus mon-
keys (Table 3, supporting information). The test compound was
administered orally prior to initiation of a challenge with DHC.
Plasma samples were isolated at various time points thereafter
and the concentration of product generated in vivo by 11-HSD-
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harvested and incubated with exogenous DHC, and the conver-
compound was preserved after 30 min of incubation for all
tested species including human, mouse, cynic, and rat.
1
2
3
4
5
6
7
8
sion of DHC to corticosterone was evaluated. The ED50 value
of 2 for inhibition of 11β-HSD-1 in this ex vivo adipose model
was determined to be 5.2 mg/kg. As compared to the ED50 value
obtained from the pharmacodynamic model, this ex vivo value
was approximately 6.5-fold more potent. This result was quali-
tatively consistent with the preference of 2 to distribute to the
adipose tissue (adipose:plasma ratio of 2 is ~ 2.5 in DIO mice).
Whole-cell patch-clamp was used to directly measure human
ether-a-go-go-related gene (hERG) potassium channel activity,
2 exhibited a slight inhibition of the hERG ion channel currents
(19.8 and 31.2% inhibition at 10 and 30 μM, respectively), pre-
dicting minimal likelihood for QT prolongation in vivo. PXR
transactivation activity was minimalwith an EC50> 50 M. Both
SOS chromotest (SOS test) and salmonella plate incorporation
test (Ames test) were negative. Single dose toxicology studies
in mice and cynomologus monkeys at oral doses up to 100
mg/kg were well tolerated except for mild emesis observed in
the monkeys.
The pharmacokinetic (PK) studies of 2 were performed in
mouse and cynomolgus monkeys. 2 distributed extra vascularly
in both species, with a steady-state volume of distribution (Vss)
of 1.2 and 2.3 L/kg in mouse and monkey, respectively. The
clearance of 2 was low in both species (mouse, 2.3 mL/min/kg;
cynomolgus monkey, 1.2mL/min/kg). Oral bioavailability from
a homogenized suspension was 44% and~100% in mouse and
monkey, respectively. Permeability of 2 in the parallel artificial
membrane permeability assay (PAMPA) was high (>500 nm/s),
suggesting that the compound is likely to be well absorbed in
humans. In the Caco-2 cells permeability assay, 2 exhibited a
B-A/A-B efflux ratio of less than 2, indicating it is unlikely to
be a substrate for efflux transporters like permeability glycopro-
tein (P-gp). For plasma protein binding (PPB), 2 was 85 %
bound to human serum proteins and 84 to 87% bound to the
serum proteins of the animal species studied (Table 5). These
encouraging pharmacokinetic results including acceptable bio-
availability and favorable half-life in different animal species
indicated that once a day (QD) oral administration should be
feasible in human clinical trials.
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Human dose projections were based on pre-clinical data from
PK studies with 2 in DIO mice. Compound 2 exhibits an in vitro
Ki of 380 nM against the mouse 11-HSD-1 enzyme and a 0.9
nM against the humanenzyme. Correcting for the species dif-
ferences in intrinsic activity and free fraction in plasma, the pre-
dicted human plasma concentrations that will lead to 50% and
90% inhibition in adipose (EC50 and EC90) are 16 nM and 146
nM, respectively.The human efficacious doses calculation was
based on maintaining the steady-state concentrations of 16 nM
(EC50) or 146 nM (EC90) at 24 h and the projected human PK
parameters (using an anticipated half-life of 32 h with a accu-
mulation ratio in humansupon repeat daily dosing of ~2), we
concluded that doses of 1 to 21 mg QD may be sufficient to
maintain the target exposures at steady state for a 70 kg human
subject.
Compound 2 also showed desirable development properties.
For example, no significant activity (IC50> 30 M) against five
major human liver cytochrome P450 isoform enzymes
(CYP3A4, CYP2C9, CYP2C19, CYP2D6 and CYP1A2) was
observed, indicating a reduced potential for drug-drug interac-
tions. Glutathione (GSH) conjugative adducts were not detected
when 2 was incubated with liver microsomes of human, mon-
key, dog, rat and mouse in the presence of nicotinamide adenine
dinucleotide phosphate hydrogen (NADPH) and GSH, suggest-
ing that reactive metabolites may not be an issue. In mice, 2
showed excellent adipose selectivity with an adipose-to-plasma
concentration ratio of 2.5 and a liver-to-plasma concentration
ratio of 3.5. The excellent partitioning of drug in adipose tissue
is particularly interesting since preclinical studies suggests that
11β-HSD-1 activity within the adipose is critical to the devel-
opment of the adverse metabolic profile related with circulating
excess endogenous glucocorticoids.16
Scheme 1. Synthesis of compound 2
An optimized discovery synthesis of 2 is illustrated in Scheme
1. The commercially available 3-bromo-2-chloropyridine 4 was
treated with hydrazine in EtOH to afford 3-bromo-2-hydrazi-
nylpyridine1-(4-chlorophenyl) 5 in 91% yield. Coupling aryl
hydrazine 5 with cyclopropane-1-carboxylic acid 6 afforded
acyl hydrazide 7, which underwent aqueous work up and was
used directly in the next step without further purification. The
crude compound 7 was treated with PEt3/CCl4/i-Pr2NEt initially
The HCl salt of 2 exhibited good intrinsic aqueous solubility
(0.50 mg/mL at pH 6.5 and 220 mg/mL at pH 1, it showed good
solid-state and oxidative solution stability as well as hydrolytic
solution stability under accelerated degradation conditions. The
compound was stable in aqueous buffers ranging from pH 1.1
to pH 7.4 for at least 1 week at 40°C with no degradation ob-
served. The crystalline solid HCl salt was found to be physically
and chemically stable for at least 12 weeks under stress condi-
o
at 0 C and then slowly warmed to room temperature over 3
o
tions, e.g. 50 C and in the presence of high intensity light/ul-
hours to give the desired cyclodehydration product 8-bromo-3-
(1-(4-chlorophenyl)cyclopropyl)-[1,2,4]triazolo[4,3-a]pyridine
8 in good yield (90%). Compound 8 was treated with n-BuLi at
traviolet (HIL/UV). 2 also showed favorable in vitro metabolic
stability in isolated microsomes testing, 96-100% of parent
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-78 oC in THF for 15 minutes to form the aryllithium interme-
diate. Subsequent addition of anhydrous acetone afforded 2 in
modest but acceptable yields (30-50%).
X-ray crystal structures for both human and mouse 11-HSD-1
complex with 2 were obtained at 2.45 Å and 2.65 Å resolution,
respectively, as shown in Figure 2 (human) and Figure 3
(mouse).17,18 The binding pose in the mouse enzyme is rotated
~180 degrees relative to the binding pose in the human enzyme.
The bulk of the differences in activity and binding pose between
the human and mouse enzymes are believed to be due to residue
177, which is a Tyr in human and a Gln in mouse, although
other residues, e.g. 231 (Val in human and Ile in mouse) and
233 (Met in human and Ala in mouse) also play a role.
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In summary, compound 2 was identified as a novel, potent, and
selective inhibitor of human 11-HSD-1 enzyme with an excel-
lent ADME profile, a desired adipose-to-plasma ratio in con-
junction with its acceptable safety attributes. Its overall favora-
ble development properties warranted advancement of 2 into
clinical Phase 1 and subsequently Phase 2 trials for the treat-
ment of type 2 diabetes and metabolic syndrome.19 The prelim-
inary human clinical trials indicated that 2 was safe and well
tolerated in healthy subjects after single and multiple oral doses
with different doses. The systemic clearance of 2 was found to
be directly correlated with the genetic polymorphism of
CYP2C19. 20
Figure 2: X-ray Crystallographic Binding Position of 2 in Human
11β-HSD1.
Acknowledgment: We thank Drs. Bruce A. Ellsworth and Pe-
ter T. Cheng for helpful suggestions during the preparation of
the manuscript.
The refined structure in the vicinity of 2 with omit mFo-DFc electron den-
sity contoured at 2.5 r.m.s.d. (cyan) and 8 r.m.s.d. (orange), which indi-
cates the location of the chlorine atom. Atom color coding carbon in 11β-
HSD1–green; 2–gray; nitrogen–blue; oxygen–red; phosphate–orange;
chlorine–split pea green. Two dimensional diagram below shows the ori-
entation of 2.
ASSOCIATED CONTENT
Supporting Information: In vitro (Table 2) and in vivo poten-
cies of 2 (Table 3); single-dose pharmacokinetic parameters
(Table 4) and physical properties of 2 (Table 5); experimental
methods for the preparation of compounds, in vitro and in vivo
assays, analytical and spectroscopic data for compounds 2, 3a-
3g, and X-ray crystallographic data of compound 2 complexed
with 11β-HSD-1. This material is available free of charge via
the internet at http://pubs.acs.org
AUTHOR INFORMATION
*Corresponding author (Jun Li) Telephone: 609-613-2288.
Email: jli137@yahoo.com
ABBREVIATIONS
11β-HSD-1, 11β-hydroxysteroid dehydrogenase type 1; DHC,
dehydrocorticosterone; TZP, Triazolopyridines; NMM, N-
Methylmorpholine; PK, pharmacokinetic; CYPs, Cytochromes
P450; PXR, Pregnane-X receptor; ADME, absorption, distri-
bution, metabolism, and excretion; DIO, diet-induced obesity
model; P-gp, permeability glycoprotein; NADPH, nicotinamide
adenine dinucleotide phosphate hydrogen; GSH, glutathione;
hERG, human ether-a-go-go-related gene; SOS test, SOS chro-
motest; Ames test, salmonella plate incorporation test.
Figure 3: X-Ray Crystallographic Binding Position for 2 in
Mouse 11β-HSD1.
The refined structure in the vicinity of 2 with omit mFo-DFc electron den-
sity contoured at 2 r.m.s.d. (cyan). Atom color coding carbon 11β-HSD1–
green; 2–gray; nitrogen–blue; oxygen–red; phosphate–orange; chlorine–
split pea green. Two dimensional diagram below shows the orientation of
2.
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