The discovery of 2-anilinothiazolones as 11β-HSD1 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2007.09.070

A series of 2-anilinothiazolones were prepared as inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The most potent compounds contained a 2-chloro or 2-fluoro group on the aniline ring with an isopropyl substituent on the 5-position of the thiazolone ring (compounds 2 and 3, respectively). The binding mode was determined through the X-ray co-crystal structure of the enzyme with compound 3. This compound was also ～70-fold selective over 11β-HSD2 and was orally bioavailable in rat pharmacokinetic studies. However, compound 3 was >580-fold less active in the 11β-HSD1 cell assay when tested in the presence of 3% human serum albumin.

Full text of DOI:10.1016/j.bmcl.2007.09.070

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 17 (2007) 6056–6061
The discovery of 2-anilinothiazolones as 11b-HSD1 inhibitors
Chester Yuan,a David J. St. Jean, Jr.,a Qingyian Liu,a Lynn Cai,a Aiwen Li,a Nianhe Han,a
George Moniz,a Ben Askew,a, Randall W. Hungate,a Lars Johansson,b Lars Tedenborg,b
David Pyring,b Meredith Williams,b,à Clarence Hale,a Michelle Chen,a Rod Cupples,a
Jiandong Zhang,a Steven Jordan,a Michael D. Bartberger,a Yaxiong Sun,a
Maurice Emery,a Minghan Wanga and Christopher Fotscha,*
aAmgen Inc., Thousand Oaks, CA 91320, USA
bBiovitrum AB, SE-112 76 Stockholm, Sweden
Received 22 August 2007; revised 19 September 2007; accepted 19 September 2007
Available online 25 September 2007
Abstract—A series of 2-anilinothiazolones were prepared as inhibitors of 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1).
The most potent compounds contained a 2-chloro or 2-fluoro group on the aniline ring with an isopropyl substituent on the 5-posi-
tion of the thiazolone ring (compounds 2 and 3, respectively). The binding mode was determined through the X-ray co-crystal struc-
ture of the enzyme with compound 3. This compound was also ꢀ70-fold selective over 11b-HSD2 and was orally bioavailable in rat
pharmacokinetic studies. However, compound 3 was >580-fold less active in the 11b-HSD1 cell assay when tested in the presence of
3% human serum albumin.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The metabolic syndrome is a cluster of cardiovascular
risk factors including visceral obesity, insulin resistance,
dyslipidemia, and hypertension.1 Features of metabolic
syndrome are also seen in patients with increased circu-
lating glucocorticoids, such as Cushing’s syndrome,2
suggesting that glucocorticoid action may play a role
in the development of metabolic syndrome. The enzyme
that increases tissue concentrations of glucocorticoids is
11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1).
Expressed mainly in liver, adipose, and the brain, 11b-
HSD1 catalyzes the conversion of inactive cortisone to
the active glucocorticoid cortisol. Elevation in tissue
cortisol levels increases glucocorticoid action.3 Although
there is no concrete evidence that patients with meta-
bolic syndrome exhibit increased circulating glucocorti-
coid levels, elevated adipose 11b-HSD1 activity has
been observed in obese humans,4 suggesting that there
is increased tissue-specific glucocorticoid action in obes-
ity. Its isoform, 11b-HSD2, is mainly expressed in the
kidney and acts as a dehydrogenase to generate corti-
sone from cortisol.5 Inhibition of this enzyme might lead
to sodium retention, hypokalemia, and hypertension,5
so inhibition of 11b-HSD2 should be avoided.
The connection between metabolic syndrome and gluco-
corticoid action was demonstrated in mouse genetic
models. Animals with elevated adipose 11b-HSD1
expression developed metabolic syndrome-like pheno-
types such as central obesity and insulin resistance.6
Moreover, mice deficient in 11b-HSD1 are resistant to
diet-induced obesity and insulin resistance.7–9 Adipose-
specific expression of 11b-HSD2 in mice, a condition
that emulates adipose-specific inhibition of 11b-HSD1,
improved insulin sensitivity, reduced adiposity, and in-
creased energy expenditure.10 Pharmacologic inhibition
of 11b-HSD1 in animal models of type 2 diabetes also
improved insulin sensitivity.11 These data indicate that
suppression of local glucocorticoid action in tissues
through inhibition of 11b-HSD1 may be a viable treat-
ment for the metabolic syndrome and type 2 diabetes.
In the last several years, 11b-HSD1 as a therapeutic
target for type 2 diabetes has stimulated a lot of interest
in the pharmaceutical industry. Mounting evidence
Keywords: 11b-Hydroxysteroid dehydrogenase type 1; 11b-HSD1;
Metabolic syndrome; Thiazolone.
*
Corresponding author. Tel.: +1 805 447 7746; fax: +1 805 480
1337; e-mail: cfotsch@amgen.com
Present address: EMD Serono, Inc., One Technology Place, Rock-
land, MA 02370, USA.
Present address: S*Bio Pte Ltd, 1 Science Park Road, #05–09 The
Capricorn, Singapore Science Park II, Singapore 117528.
à
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.09.070

C. Yuan et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6056–6061
6057
man 11b-HSD1.29 Results are reported as the average
of at least two independent experiments with at least
two replicates at each concentration. The variance in
the measurements is expressed as the standard error of
the mean (SEM).
H
N
O
N
S
1
11β-HSD1 Ki = 110 nM
In general, compounds with small groups on the 2-posi-
tion of the phenyl ring were more potent than the parent
compound 1. For example, compounds containing the
2-chloro, 2-fluoro, 2-methyl or 2-trifluoromethyl groups
were all potent with Ki values of <40 nM (see com-
pounds 2–5, Table 1). The analog with the larger 2-
methoxyl group, compound 6, was >25-fold less potent
than compounds 2–5. The 4-fluoro analog, compound 7,
was 20-fold less potent than its ortho-substituted analog
2. Other analogs containing groups at the 4-position
(e.g., phenoxyl and cyclohexyl substituted compounds
8 and 9) were also significantly less potent than the par-
ent compound 1. Additional analogs were prepared
where the 2-chloro or 2-fluoro groups were retained
and an additional group was added to the aromatic ring
(see compounds 10–13, Table 1). For all of these ana-
logs, the potency was within twofold of the potency ob-
served for the mono-substituted compounds 2 and 3.
Generally, the cellular potencies for this set of com-
pounds were within two- to threefold of the potency ob-
tained in the biochemical assay, indicating that these
compounds had good cell permeability and could read-
ily access the active site of the enzyme in the lumen of
the endoplasmic reticulum.
Figure 1. 2-Anilinothiazolone compound 1.
obtained from preclinical studies supports the concept
that inhibiting 11b-HSD1 may have a therapeutic bene-
fit by lowering hepatic glucose output and increasing
insulin sensitivity.12,13 Many patent applications and
studies on 11b-HSD1 inhibitors illustrate the intense
interest in this field.14–27 In this publication, we describe
some of our efforts to identify potent, selective, and bio-
available inhibitors of 11b-HSD1.
Compound 1, with a Ki = 110 nM, was identified from
the high-throughput screening of our internal com-
pound collection (Fig. 1). This compound represented
a new class of 11b-HSD1 inhibitors with an unknown
binding mode at that time. Initial structure–activity rela-
tionship (SAR) exploration included modification of the
phenyl moiety to include substituted phenyl and het-
eroaromatic rings. The isopropyl group of 1 was then re-
placed with various lipophilic groups. Our synthetic
strategy entailed two approaches allowing for rapid
modification of either region of the molecule.27 The first
route used the reaction between 2-bromoalkanoyl isoth-
iocyanates and anilines to form thiazolones under basic
conditions (Scheme 1, step c). The 2-bromoalkanoyl
isothiocyanates were prepared from the corresponding
2-bromoalkanoyl acid chlorides and potassium thiocya-
nate (Scheme 1, step b). The second route involved the
cyclization between a thiourea and 2-alkyl-2-bromoace-
tate in presence of N,N0-diisopropylethylamine under
microwave irradiation at 120 ꢁC (Scheme 1, step d).
The compounds were prepared and tested as racemates
unless mentioned otherwise.
We then replaced the aryl ring with various heteroaro-
matic groups (see Table 2). Replacing the phenyl group
with either 2- or 4-pyridinyl ring (compounds 14 and 15)
resulted in a 23- and 45-fold loss in potency, respectively
(compared to analog 1). Three 5,6-membered ring het-
erocycles were prepared (see compounds 16–18). The
most potent in this set was the 1H-indol-4-yl analog
Table 1. SAR of the phenyl ring on compound 1
O
Inhibition of 11b-HSD1 and 11b-HSD2 enzymatic
activity was determined using a scintillation proximity
assay (SPA).14,28 Cell-based activity was measured by
monitoring the conversion of cortisone to cortisol in
Chinese hamster ovary cells stably transfected with hu-
N
R
S
N
H
Compound
R
11b-HSD1
11b-HSD1
Ki (SPA) (nM)a IC50 (cell) (nM)a
1
H
2-Cl
110 10
7.2 2.2
310 90
10
O
O
a, b
2
2
Br
Br
OH
Ar
N C S
3
2-F
2-Me
17
27
23
1
5
3
50 31
120 60
28 11
R2
R2
4
5
2-CF3
2-OMe
4-F
6
1000 200
340 100
220 13
1500 270
230 70
c
S
7
8
4-OPh
4-Cyclohexyl
2-Cl, 4-Cl
2-Cl, 6-Cl
2-F, 5-F
2-F, 4-F
O
H
N
N
NH2
N
9
660 190
3300 1800
40 18
O
H
Br
10
11
12
13
18
13
12
26
9
2
1
3
O
Ar
d
S
R2
21
7
R2
28 10
45 16
Scheme 1. Reagents and conditions: (a) oxalyl chloride, CH2Cl2, rt; (b)
KSCN, acetone, rt; (c) ArNH2, triethylamine, CH2Cl2; (d) N,N0-
diisopropylethylamine, EtOH, microwave, 120 ꢁC.
a Values are reported as the avg. SEM. For assay details, see Refs.
28,29.

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C. Yuan et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6056–6061
Table 2. SAR of heteroaromatic rings in place of the phenyl ring on
compound 1
isopropyl analog 2. Analogs in the 2-chlorophenyl series
with a larger C-5 group, that is, cyclohexyl or cyclopen-
tyl analogs 21 and 22, had potencies very similar to the
isopropyl analog 2 (Kis from 6 to 11 nM). For the 2-flu-
orophenyl series, the cyclohexyl or cyclopentyl analogs
23 and 24 showed a slight improvement in potency over
the isopropyl analog 3. Interestingly, the 2-chlorophenyl
analogs 21 and 22 were more selective for 11b-HSD1
over 11b-HSD2 than the 2-fluorophenyl analogs, 23
and 24 (420- and 710-fold for 2-chloro analogs 21 and
22, respectively, vs. ꢀ70-fold for 2-fluorophenyl analogs,
23 and 24).
O
N
Ar
S
N
H
Compound Ar
11b-HSD1
11b-HSD1
Ki (SPA) (nM)a IC50 (cell) (nM)a
14
15
16
17
Pyridin-2-yl
4900 300
2500 900
1000 150
510 10
1400 400
To better understand the interactions between the lead
compounds with the active site of 11b-HSD1, the ter-
nary X-ray co-crystal structure of compound 3,
NADPH, and human 11b-HSD1 was determined using
conditions previously described.30 The overall fold and
other structural features of the dimeric, crystallized
11b-HSD1 protein have been previously discussed.30
Compound R-3 interacts with a single monomer of the
dimeric 11b-HSD1 and forms several key interactions
with the amino acids located in the active site (Fig. 2).
Only the R-enantiomer of compound 3 formed a com-
plex with the enzyme, which is consistent with the activ-
ities of the separated isomers of 3, where R-3 was found
to be 20-fold more potent than S-3 (see Table 4). The
isopropyl function of R-3 occupies a large hydrophobic
pocket comprised primarily of Thr124, Leu126, Tyr183,
and Ala223 (some residues not shown for clarity). The
Pyridin-4-yl
N
1500 400
N
H
N
S
18
19
210 14
360 130
200 70
N
H
32
9
N
a Values are reported as the avg. SEM. For assay details, see Refs.
28,29.
˚
isopropyl-bearing methine carbon of R-3 is 3.79 A from
the pendant amide carbonyl carbon of NADPH in the
co-crystal structure. If the stereoisomer S-3 were to
bind, a steric clash with the NADPH cofactor would oc-
cur, which may be why S-3 is less potent than R-3.
which had a Ki = 210 nM. The most potent heteroaro-
matic compound prepared was the 5-isoquinolinyl ana-
log 19, which had a Ki = 32 nM. However, compound
19 had a cell IC50 sixfold less potent than the SPA Ki,
which may indicate that this compound did not pene-
trate the cell as well as other analogs in this series.
Table 4. Activity of compound 3 and its separated enantiomers36
Compound
11b-HSD1
11b-HSD1
Having found that the 2-chloro and 2-fluoro groups on
the phenyl ring improved potency, we kept this group
constant while exploring the SAR of the C-5 substituent
(see Table 3). In the 2-chlorophenyl series, the C-5
methyl analog 20 was 49-fold less potent than the C-5
Ki (SPA) (nM)a
IC50 (cell) (nM)a
3
17 12
50 31
R-3
S-3
7
140 30
1
15
97 42
4
Table 3. SAR of 5-alkyl groups on compounds 2 and 3
O
N
R2
S
N
H
X
Compound
X
R2
11b-HSD1 Ki (SPA) (nM)a
11b-HSD1 IC50 (cell) (nM)a
11b-HSD2 IC50 (SPA)(nM)a
20
2
Cl
Cl
Cl
Cl
F
Me
350 70
7.2 2.2
Isopropyl
Cyclohexyl
Cyclopentyl
Isopropyl
Cyclohexyl
Cyclopentyl
10
33
17
2
9
7
2510 600
4600 3400
4500 3500
21
22
3
11
6.3 2.7
17
5
1
50 31
43 10
19 11
23
24
F
7.2 2.3
5.3 1.2
530 310
380 190
F
a Values are reported as the avg. SEM. For assay details, see Refs. 28,29.

C. Yuan et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6056–6061
6059
Turning to the other regions of the molecule, the car-
˚
bonyl group of R-3 interacts (2.96 A) with a bound
water molecule near the solvent exposed region of the
protein. Additionally, the phenyl ring is perpendicular
to the plane of the thiazolone core, maximizing conjuga-
tion with the exocyclic nitrogen lone pair and forming
an edge-to-face (T-shaped) aromatic stacking interac-
tion33 (ca. 4 A) with the phenyl moiety of Tyr177. The
˚
2-fluoro substituent is thought to aid in potency through
both enhanced van der Waals contacts within the active
site, as well as enhancement of the interaction between
the adjacent, meta aryl C–H and the electron-rich p-face
of Tyr177.34 Through site-directed mutagenesis studies,
we have previously shown that Tyr177 is also an impor-
tant residue for binding the licorice derived inhibitor,
glycyrrhetinic acid.35
To test whether these compounds could be used for
in vivo studies, the rat pharmacokinetics for some
of our most potent compounds were determined (see
Table 5). For compounds 3–5, the in vivo clearance
(CL) was well below liver blood flow, and for com-
pounds 4 and 5, the oral bioavailability was >70%.37
The volume of distribution (Vss) was less than the CL
for all three of these compounds which resulted in
half-lives of less than 1 h. The plasma protein binding
(PPB) for compounds 4 and 5 was >99%, which might
explain the low Vss. To assess the impact of PPB on po-
tency for this set of compounds, the cellular assay was
run in the presence of 3% human serum albumin
(HSA) to mimic the in vivo concentration of albumin.
In all three cases, the whole cell IC50s in the presence
of 3% HSA were >1 lM, which represents a 10–580-fold
loss in activity. The high protein binding and its effect on
potency and half-life may limit the in vivo efficacy of
these compounds in rats.
Figure 2. Key binding interactions of compound 3 (cyan) with human
11b-HSD1. Active site residues are depicted in green, NADPH in
purple. Bound active site water is depicted in red.
From the hydrogen bonding interactions of the OH
groups on Ser170 and Tyr183 with R-3, it is apparent
that R-3 existed as the exo-tautomer (see Fig. 2).31 In
the X-ray structure, the CH2OH side chain of Ser170
is oriented syn to residues Leu171 and Ala172, with
the side chain oxygen atom located at a distance of
˚
2.64 and 2.96 A from the respective backbone NH nitro-
gen atoms of these residues (see Fig. 2.) In this orienta-
tion, the lone pairs of the side chain oxygen of Ser170
function as acceptors to the Leu171 and Ala172 back-
bone NH protons, leaving the Ser170 OH proton to
interact with the imine-like nitrogen of the exocyclic
double bond tautomer of R-3.32 Compound R-3 forms
a hydrogen bond between the endocyclic NH and the
side chain oxygen on Tyr183. The hydrogen on the side
chain hydroxyl of Tyr183 may interact with either a ri-
bose OH oxygen of NADPH and/or solvent waters.
In summary, from the lead 2-anilinothiazolone 1, we
identified several compounds that have Kis < 10 nM.
The most potent compounds in this series had
IC50s < 50 nM in a whole cell assay and were at least
70-fold more selective for 11b-HSD1 over 11b-HSD2.
As revealed through an X-ray structure of lead com-
pound 3 with 11b-HSD1, this molecule binds as the
exo tautomer, forms hydrogen bonding interactions
with Ser170 and Tyr183, and forms a hydrophobic,
edge-to-face stacking interaction with Tyr177 within
Table 5. Rat pharmacokinetics, protein binding, and protein shift of selected 2-anilinothiazolones
O
N
S
N
H
X
Compound
X
CL (L/h/kg)a Vss (L/kg)a t1/2 (h)a %Fb %PPBc Cell IC50 with 0% HSA (nM) Cell IC50 with 3% HSA (lM)
3
4
5
F
Me
0.30
1.30
0.16
0.42
0.54
0.84
1.23
1.35
nd
87
73
nd
50
>10
1.3
99.6
99.8
120
28
CF3 0.76
2.0
a Dosed IV (0.5 mg kgꢁ1) in DMSO.
b Dosed PO (2.0 mg kgꢁ1) in 0.5% CMC/0.1% Tween 80 in water.
c Human plasma protein binding measured by equilibrium dialysis.

6060
C. Yuan et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6056–6061
Marsh, K. C.; Beno, D. W. A.; Fey, T. A.; Droz, B. A.;
Brune, M. E.; Camp, H. S.; Sham, H. L.; Frevert, E. U.;
Jacobson, P. B.; Link, J. T. J. Med. Chem. 2007, 50, 149.
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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.
17. Richards, S.; Sorensen, B.; Jae, H.; Winn, M.; Chen, Y.;
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the active site. The rat pharmacokinetic profile for some
of these compounds had moderate to low clearance and
oral bioavailability >70%. However, there was a 10–580-
fold loss in activity when the whole cell assay was run in
the presence of 3% HSA for compounds 3–5. The data
reported here on the 2-anilinothiazolones complement
the SAR we previously reported on benzyl thiazolone
analogs.14 Additional SAR on the thiazolone core struc-
ture will be reported in due course.
Supporting information: X-ray data have been deposited
in the RCSB Protein Data Bank (www.rcsb.org). PDB
ID: 2RBE.
18. Yeh, V. S. C.; Kurukulasuriya, R.; Fung, S.; Monzon, K.;
Chiou, W.; Wang, J.; Stolarik, D.; Imade, H.; Shapiro, R.;
Knourek-Segel, V.; Bush, E.; Wilcox, D.; Nguyen, P. T.;
Brune, M.; Jacobson, P.; Link, J. T. Bioorg. Med. Chem.
Lett. 2006, 16, 5555.
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31. B3LYP/6-31G* + SCRF solvation calculations also pre-
dict the exocyclic double bond tautomer of 3 to be the
dominant species in aqueous solution.32
32. The tautomeric equilibria of N-substituted thiazolones
appear highly dependent on the nature of the substituent.
A detailed study of tautomerism in this and other related
systems, along with ramifications of ligand binding, will be
published in due course.
14. St. Jean, D. J., Jr.; Yuan, C.; Bercot, E. A.; Cupples, R.;
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36. Compound 3 was separated using preparative supercritical
fluid chromatography (SFC). Eluant: 55:45 CO2(l)/
CH3OH; column: Chiralpak AD-H (250 · 21 mm, 5 lm);
flow rate: 65 mL/min; column temp: 40 ꢁC.
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37. Compounds 3–5 are racemates and it is possible that the
single enantiomers may have different PK. However, the
protein shift was not significantly different for the sepa-
rated enantiomers.