Synthesis and optimization of arylsulfonylpiperazines as a novel class of inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)

Article abstract of DOI:10.1016/j.bmcl.2008.12.114

The synthesis and SAR of a series of arylsulfonylpiperazine inhibitors of 11β-HSD1 are described. Optimization rapidly led to potent, selective, and orally bioavailable inhibitors demonstrating efficacy in a cynomolgus monkey ex vivo enzyme inhibition model.

Full text of DOI:10.1016/j.bmcl.2008.12.114

Bioorganic & Medicinal Chemistry Letters 19 (2009) 1522–1527
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and optimization of arylsulfonylpiperazines as a novel class
of inhibitors of 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1)
*
Daqing Sun , Zhulun Wang, Mario Cardozo, Rebekah Choi, Michael DeGraffenreid, Yongmei Di, Xiao He,
Juan C. Jaen , Marc Labelle à, Jinsong Liu, Ji Ma, Shichang Miao , Athena Sudom, Liang Tang, Hua Tu,
Stefania Ursu, Nigel Walker, Xuelei Yan, Qiuping Ye, Jay P. Powers
Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and SAR of a series of arylsulfonylpiperazine inhibitors of 11b-HSD1 are described. Optimi-
zation rapidly led to potent, selective, and orally bioavailable inhibitors demonstrating efficacy in a cyno-
molgus monkey ex vivo enzyme inhibition model.
Received 18 October 2008
Revised 23 December 2008
Accepted 31 December 2008
Available online 9 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
11b-HSD1
11b-HSD2
Diabetes
Metabolic syndrome
Hydroxysteroid dehydrogenase
Arylsulfonylpiperazines
11b-Hydroxysteroid dehydrogenase type 1 (11b-HSD1) is a key
enzyme that acts as an NADPH-dependent reductase capable of
converting inactive 11b glucocorticoids such as cortisone into their
active form, (e.g., cortisol), in specific tissues, such as liver, adipose,
and brain tissues. Therefore, 11b-HSD1 regulates tissue-specific
glucocorticoid levels.1–4 Conversely, 11b-hydroxysteroid dehydro-
genase type 2 (11b-HSD2), a structurally related isoenzyme of
11b-HSD1, catalyzes the conversion of cortisol to cortisone utiliz-
ing NAD as a cofactor. 11b-HSD2 is expressed in cells that contain
the mineralocorticoid receptor (MR) and protects the MR by con-
verting cortisol to the inactive form, cortisone.5 Selective inhibition
of 11b-HSD1 may be a viable therapeutic strategy for the treatment
of metabolic syndrome and has attracted significant attention from
the pharmaceutical research community.6–13
We previously reported arylsulfonylpiperazines as potent
inhibitors of 11b-HSD1 in in vitro assays.14,15 Although compound
1 (Fig. 1) exhibited excellent in vitro inhibition of human and
mouse 11b-HSD1, it had poor water solubility and oral bioavail-
ability in rats. In this communication, we described our optimiza-
tion efforts on structural modifications of 1 to improve the potency
NO2
N
N
hHSD1 IC50 = 10 nM
h293 IC50 = 247 nM
mHSD1 IC50 = 161 nM
rat PK:
CL: 1.0 L/h/Kg
%F: 7
S
O
O
1
Figure 1. Arylsulfonylpiperazine 11b-HSD1 inhibitor.
and pharmacokinetic (PK) profiles of this class of arylsulfonylpiper-
azine 11b-HSD1 inhibitors. These efforts led us to the discovery of
potent, selective, and orally bioavailable inhibitors showing excel-
lent efficacy in a cynomolgus monkey ex vivo enzyme inhibition
model.
Compounds were synthesized via the routes outlined in
Schemes 1–5.16 Compounds 2–8, 18–21, and 30, were prepared
as shown in Scheme 1. Compounds 2–8 were obtained simply by
reaction of tert-butylbenzenesulfonyl chloride and N-alkylpiper-
azine 31, which was synthesized by either direct nucleophilic
displacement between the alkyl halide and (R)-(À)-2-methylpiper-
azine or reductive amination of (R)-(À)-2-methylpiperazine with
the appropriate aldehyde. Treatment of 31 with 4-acety-
lbenzenesulfonyl chloride in dichloromethane provided the
* Corresponding author. Tel.: +1 650 244 2195.
E-mail address: daqings@amgen.com (D. Sun).
Present address: ChemoCentryx, Inc., Mountain View, CA 94043, USA.
Present address: Lundbeck Research USA, Inc., 215 College Road, Paramus,
à
NJ 07652, USA.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.12.114

D. Sun et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1522–1527
1523
RCl
a
As shown in Scheme 2, compounds 9–15 were prepared from
methyl ketone 32 using standard functional group transforma-
tions. Intermediate 32 was obtained by treatment of 4-acety-
lbenzenesulfonyl chloride with piperazine 31, which was derived
from direct nucleophilic displacement between 4-pyridylethyl
chloride and (R)-(À)-2-methylpiperazine. Addition of methyl lith-
ium to 32 formed alcohol 9, which was subsequentially fluorinated
with DAST in dichloromethane at À78 °C to afford 10. Treatment
with TMS-CF3 converted 32 to trifluoromethylcarbinol 11, which
was fluorinated with DAST to afford 12. Reduction of 32 with
NaBH4 provided 13, which was converted to 14 with excess DAST
at room temperature. In a similar fashion, compound 15 was pre-
pared by treating 32 with DAST.
R
R
N
c
N
NH
HN
d
N
HN
S
b
O
O
2-8
31
RCHO
e
CF3
HO
R
N
N
S
O
O
18-21, 30
The synthetic route for preparing compounds 16–17 is shown
in Scheme 3. Treatment of 31 with sulfonyl chloride 33 in dichlo-
romethane gave the ester, which was then reduced with DIBAL-H
to yield the alcohol 16. Oxidation of the primary alcohol in 16, fol-
lowed by reductive amination of the resulting aldehyde with mor-
pholine gave 17.
Scheme 1. Reagents and conditions: (a) MeCN, 100 °C, 45–75%; (b) NaBH(OAc)3,
acetic acid, CH2Cl2, 54–92%; (c) 4-tert-butylbenzenesulfonyl chloride, Et3N, CH2Cl2,
65–84%; (d) 4-acetylbenzenesulfonyl chloride, Et3N, CH2Cl2, 52–74%; (e) TMS-CF3,
TBAF, THF, 60–75%.
X
R
13, X = OH
14, X = F
N
N
f
N
S
( )n
( )n
O
e
O
b
c
a
OEt
OEt
Cl
Ar
Ar
Ar
O
34
O
35
36
O
CF3
X
R
d
R
c
N
CF3
N
HO
N
S
Ar
( )n
Ar
( )n
S
e
N
N
O
O
O
O
N
HN
32
f
S
11, X = OH
O
O
d
g
37
a
12, X = F
22-27, n = 0, 1, 2
X
R
N
Scheme 4. Reagents and conditions: (a) NaH, BrCH2(CH2)nCH2Br, 49–80%; (b)
DIBAL-H, THF, 49–54%; (c) SOCl2, 83–84%; (d) (R)-(À)-2-methylpiperazine, MeCN,
100 °C, 75–83%; (e) 4-acetylbenzenesulfonyl chloride, Et3N, CH2Cl2, 61–74%; (f)
TMS-CF3, TBAF, THF, 20–57%.
F
N
F
S
R
N
O
O
N
9, X = OH
S
O
O
b
15
10, X = F
O
( )n
( )n
N
c
N
OEt
OEt
a
b
EtO
OEt
OEt
HO
R =
HN
( )n
O
O
O
O
Scheme 2. Reagents and conditions: (a) MeLi, THF, 25%; (b) DAST, CH2Cl2, 21%; (c)
TMS-CF3, TBAF, THF, 63%; (d) DAST, CH2Cl2, 40%; (e) NaBH4, MeOH, 92%; (f) DAST,
CH2Cl2, 42%; (g) DAST, 25%.
40
39
38
d
e
CF3
O
N
f, g
N
( )n
S
R
EtO
N
a
b
O
O
OH
N
O
41
S
SO2Cl
CF3
O
O
O
HO
33
16
N
NH2
N
( )n
S
c
d
O
O
28-29, n = 0, 1
R
N
CF3
HO
O
N
N
O
N
S
h
O
O
R =
N
NH2
+ (R)-28
28
N
17
S
O
O
Scheme 3. Reagents and conditions: (a) 31, Et3N, CH2Cl2, 93%; (b) DIBAL-H, THF,
92%; (c) Dess–Martin periodinane, THF, 53%; (d) Morpholine, NaBH(OAc)3, acetic
acid, CH2Cl2, 27%.
(S)-28
Scheme 5. Reagents and conditions: (a) LiAl(OtBu)3H, THF, 46%; (b) Dess–Martin
periodinane, THF, 70%; (c) (R)-(À)-2-methylpiperazine, NaBH(OAc)3, acetic acid,
CH2Cl2, 80%; (d) 4-acetylbenzenesulfonyl chloride, Et3N, CH2Cl2, 53%; (e) TMS-CF3,
THF, 78%; (f) LiOH, THF/MeOH/H2O, 86%; (g) (i) SOCl2; (ii) NH3, 60%; (h)
diastereoisomer separation.
corresponding ketone, which was converted to compounds 18–21,
17
30, respectively, via treatment with TMS-CF3.

1524
D. Sun et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1522–1527
Table 1
The synthesis of compounds 22–27 is depicted in Scheme 4.
Inhibition of 11b-HSD1 by selected analogs: N-alkylation
Commercially available ester 34 was alkylated with appropriate
dibromide to give 35. Reduction of 35 with DIBAl-H, followed by
chlorination of the primary alcohol with thionyl chloride produced
chloride 36, which was then coupled with (R)-(À)-2-methylpiper-
azine to yield 37. Finally, preparations of compounds 22–27 were
achieved by treatment of 37 with 4-acetylbenzenesulfonyl chlo-
ride, followed by trifluoromethylation with TMS-CF3.
R
N
N
S
O
O
Compound
R
h-HSD1a IC50
(nM)
h-293a IC50
(nM)
Solubility (lg/
mL) pH 5.0
In Scheme 5, reduction of the appropriate ester 38 with lithium
tri-tert-butoxyaluminohydride formed the corresponding alcohol,
which was then oxidized to the aldehyde 39 with Dess–Martin
periodinane. Reductive amination of 39 with (R)-(À)-2-methylpi-
perazine gave the substituted piperazine 40, which was succes-
sively treated with 4-acetylbenzenesulfonyl chloride and
trifluoromethylation with TMS-CF3 to provide the ester 41. Hydro-
lysis of 41 with lithium hydroxide gave the acid, which was treated
with thionyl chloride and then ammonia to yield 28 or 29, respec-
tively. Separation of the diastereoisomers of 28 via preparative chi-
ral HPLC (Chiralpak AD) afforded optically pure (S)-28 and (R)-28.
Compounds were evaluated for the inhibition of human and
mouse 11b-HSD1 enzymes, as well as in cell-based assays. 11b-
HSD1 enzyme activity was determined by measuring the conver-
sion of [3H]-cortisone to [3H]-cortisol. Product [3H]-cortisol, cap-
tured by an anti-cortisol monoclonal antibody conjugated to
scintillation proximity assay (SPA) beads, was quantified with a
microscintillation plate reader. Biochemical enzyme assays were
performed with Baculovirus-produced recombinant full-length hu-
man 11b-HSD1 as the enzyme source and NADPH as cofactor (h-
2
3
57
146
61
1.8
NO2
3
4
5
6
7
11.3
5.3
1
18.1
21.8
39
N
N
N
47
3.4
94
96
20.8
—
N
N
Ph
825
HSD1 IC50). Cell-based enzyme assays (h-293 IC50
) utilized
HEK293 cells stably expressing recombinant human full-length
11b-HSD1 as the enzyme source without supplementation of
NADPH. IC50 values for enzyme inhibition were calculated with a
dose–response curve fitting algorithm with at least duplicate sets
of samples.
8
7.3
78
1.0
N
a
Values are means of at least two determinations.
Our initial optimization efforts began with the goal of improv-
ing the solubility of 1 by incorporating a carbon spacer between
the aryl group and the piperazine ring. As shown in Table 1, the
4-pyridyl compounds (3, 4, 5, and 6), which have a carbon based
spacer, showed significant improvement in water solubility com-
pared to 1 and 2. Additionally, two or three-carbon spacers (4
biochemical potency, but a decrease in cellular potency and
in vitro metabolic stability as compared to 11 and 18, respectively.
As N-dealkylation was observed as a significant metabolic lia-
bility in vitro, further investigation was carried out to introduce
a cycloalkyl ring in the a-position of 11 and 18. As indicated in Ta-
and 5) and methyl substitution at the
group (6) resulted in potency similar to 2. However, phenyl substi-
tution at the -position (7) notably reduced potency. The incorpo-
ration of an additional fused benzene ring (8) brought a slight
decrease in potency as compared to 3. These data suggested that
a-position of the 4-pyridyl
ble 4, addition of a cycloalkyl ring gave a significant increase in bio-
chemical potency with cyclopropyl, cyclobutyl, and cyclopentyl
substituents (examples 22–27, h-HSD1 IC50 < 1 nM), while cellular
potency was mostly maintained relative to 11 and 18. Further-
more, compound 22 also displayed significant improvement in
in vitro metabolic stability over 11 (80% vs 59% remaining in rat li-
ver S9 @ 60 min). The rat PK profile of 22 featured good oral bio-
availability and a moderate clearance (F = 60%; CL = 2.1 L/h/kg).
However, compound 22 also exhibited strong in vitro inhibitory
activity against hERG and CYP-3A4 (Table 5).
In order to diminish the hERG and CYP-3A4 liability, alignment
of pyridine analog 22 to a hERG pharmacophore model18 was used
to design modifications aimed at reducing hERG potency. Potent
hERG blockers such as 22 aligned to the pharmacophore by match-
ing two hydrophobic features and the ionizable nitrogen (Fig. 2)
present in the inhibitors. This alignment suggested potential mod-
ifications to reduce the hERG liability. Replacement of the pyridine
moiety, which matches one of the hydrophobic features, with polar
groups were explored. Thus, compound 28 with an amide group
replacing the pyridyl ring, was a much weaker hERG blocker than
a
both spacer length and substitution at the a-position were impor-
tant for 11b-HSD1 inhibitory activity.
Based on metabolic liabilities we observed in our previous
efforts,14 i.e., in vitro oxidation of the tert-butyl group, we next
turned our attention to modification of the substitution at the 4-
position of the sulfonamide phenyl ring. Table 2 shows the effects
of varying substituents at the 4-position of 4. It was found that the
trifluoromethylcarbinol moiety (11) produced approximately a
threefold improvement in biochemical and cellular potency over
the corresponding tert-butyl analog 4, along with even more signif-
icant improvement in metabolic stability. No in vitro metabolite
derived from the trifluoromethylcarbinol moiety was observed in
metabolite identification studies.
With the discovery of the improved potency and metabolic sta-
bility imparted by the trifluoromethylcarbinol group as a substitu-
ent at the 4-position of the sulfonamide phenyl ring, we then
returned to investigate further modifications of the N-alkyl substit-
uents in 11. The data in Table 3 indicated that 3-pyridyl derivative
18 was as potent as 11, while the corresponding 2-pyridyl analog
19 exhibited decreased potency. Interestingly, the incorporation
22 (hERG IC50 22; 0.44 lM ? 28; >100 lM, Table 5). Additional
modifications were made by adding hydrogen bond donor groups
to the terminal aromatic ring targeting the so-called anti-hERG fea-
ture. Compound 30 with an amide at the para-position of phenyl
ring, was a weak hERG blocker with an IC50 of 6.4 lM. Figure 2
of fluorines to the
a-position (20, 21) brought a slight increase of

D. Sun et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1522–1527
1525
Table 2
Table 4
Inhibition of 11b-HSD1 by selected analogs: sulfonamide aryl modification
In vitro inhibition and metabolic stability data for analogs 22–27
CF3
HO
N
R
N
R
N
N
N
S
S
O
O
O
O
Compound
R
h-HSD1a IC50 h-293a IC50
Rat S9% remaining
after 60 min
Compound
R
h-HSD1a IC50 (nM)
h-293a IC50 (nM)
61
(nM)
(nM)
33
4
5.3
5
22
0.4
80
N
N
HO
F
9
10
11
12
13
14
15
69
—
23
24
25
26
0.5
0.6
0.5
0.8
0.6
27
43
27
35
30
50
54
61
43
60
36
2.2
4
CF3
HO
21
71
70
CF3
N
N
F
OH
12
16
30
F
138
86
F
N
N
F
27
16
4
8
55
OH
a
Values are means of at least two determinations.
17
505
N
O
Table 5
CYP-3A4 and hERG inhibition potency of selected analogs
a
Values are means of at least two determinations.
CF3
HO
N
R
Table 3
N
S
In vitro inhibition and metabolic stability data for analogs 18–21
O
O
CF3
HO
Compound
R
h-HSD1a IC50
(nM)
3A4 IC50
M)
hERG IC50
(lM)
N
R
(l
N
S
O
O
2
0.42
1.7
0.44
0.44
Compound
R
h-HSD1a IC50
(nM)
h-293a IC50
(nM)
Rat S9% remaining
after 60 min
N
NH2
28
29
>100
65
>100
65
11
18
19
20
2.2
1.3
10
21
29
59
67
28
40
O
O
N
N
NH2
3.0
N
131
33
30
1.2
—
6.4
CONH2
Values are means of at least two determinations.
F
F
F
a
0.9
N
N
F
illustrates the alignment of compounds 22, 28, and 30 against the
hERG and anti-hERG pharmacophores.
21
1.1
78
46
Separation of the diastereoisomers of 28 was achieved by pre-
parative chiral HPLC (Chiralpak AD) to afford the optically pure
a
Values are means of at least two determinations.

1526
D. Sun et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1522–1527
(S)-28, a highly potent (hHSD1 IC50 = 0.7 nM) inhibitor of 11b-
HSD1with excellent selectivity (hHSD2 IC50 > 100 M) and no
hERG and CYP liabilities (Table 6). Compound (S)-28 also exhibited
significant improvements in water solubility and oral bioavailabil-
ity in rats compared to 1 (Table 7).
In addition to the excellent potency and pharmacokinetic pro-
file of compound (S)-28, this molecule had suitable activity against
cynomologous monkey 11b-HSD1 enzyme (IC50 = 6 nM) and was
selected for further evaluation in our cynomolgus monkey
ex vivo pharmacodynamic model. In this study, cynomolgus
monkeys were dosed orally with 0.4, 2, and 10 mg/kg of inhibitor
(S)-28. At 2 h post-dose, mesenteric fat tissues were collected.
Following 1 h incubation of these tissues in media containing
[3H]-cortisone, 11b-HSD1 activity was measured through detection
of tritiated cortisol levels using a scintillation proximity assay. Rel-
ative to controls, all dose groups showed a decrease in [3H]-cortisol
production in mesenteric fat (Fig. 3), corresponding to an ED50 in
Mesenteric fat 11β-HSD1 activity
l
8
6
4
2
0
p=0.075
p=0.04
0
0.4
2
10
(mg/kg)
Figure 3. Ex vivo 11b-HSD1 enzyme activity in intact mesenteric fat collected from
cynomolgus monkeys orally dosed with compound (S)-28. Plasma and mesenteric
fat samples were collected 2 h after compound was administered orally in dosing
vehicle (1% methylcellulose and 1% Tween 80 in sterile water). 11b-HSD1 enzyme
activity was measured as the [3H]-cortisol formed after 1 h incubation of fat
samples in reaction buffer containing [3H]-cortisone at 37 °C. Compound concen-
tration in plasma and fat samples was determined with LC/MS/MS bio-analytic
method.
cynomolgus monkey of 0.4 mg/kg. These results demonstrate that
(S)-28 is effective in lowering 11b-HSD1 adipose activity in cyno-
molgus monkeys when administered orally. Compound exposure
levels in this experiment were measured to be considerably higher
in adipose than in plasma (Table 8), demonstrating that inhibitor
(S)-28 effectively distributed to the target tissue.
Finally, insight into the binding mode of this class of 11b-HSD1
inhibitors was obtained by X-ray crystallography (Fig. 4).21 The co-
Table 8
Plasma and fat tissue exposure in cynomolgus monkeys after oral dosing with (S)-28
Po dose
N
[(S)-28] (
l
M) Plasma
[(S)-28] (lM) Mesenteric fat
Vehicle
4
3
3
3
BQL
BQL
0.4 mg/kg
2 mg/kg
10 mg/kg
0.029 0.009
0.349 0.133
0.503 0.131
0.105 0.036
2.779 1.537
40.747 20.874
Figure 2. Alignment to hERG/anti-hERG pharmacophore.
Table 6
In vitro 11b-hSD1, CYP-3A4, and hERG inhibition potency of 28, (S)-28, and (R)-28
Compound h-HSD1a IC50
(nM)
h-293a IC50
(nM)
3A4 IC50
M)
hERG IC50
M)
(
l
(l
28
(S)-28
(R)-28
1.7
0.7
7.9
25.4
14
128
>100
>100
>100
>100
>100
>100
a
Values are means of at least two determinations.
Table 7
Solubility and rat PK data of 1 and (S)-28
Compound
AUC (po,
g h/L)
CL (iv,
L/kg/h)
F (po, %)
Solubility (
pH 5.0
lg/mL)
l
Figure 4. Co-crystal structure of compound (S)-28 in human 11b-HSD1. The protein
is shown in both stick and molecular surface representations which are color coded
(red for oxygen atoms, blue for nitrogen, orange for sulfur, and slate for carbon). The
inhibitor and the cofactor NADP+ are shown in sticks and color coded gray for
carbon atoms in NADP+ and green for the inhibitor.
1
29.8
638
1.0
1.4
7
41
0.5
>48.1
(S)-28
Dosed iv 0.5 mg/kg, po 2.0 mg/kg.

D. Sun et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1522–1527
1527
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Sudom, A.; Sun, D.; Tu, H.; Ursu, S.; Walker, N.; Yan, X.; Ye, Q.; Powers, J. P.
J. Med. Chem. 2008, 51, 3953.
14. Sun, D.; Wang, Z.; Di, Y.; Jaen, J. C.; Labelle, M.; Ma, J.; Miao, S.; Sudom, A.; Tang,
L.; Tomooka, C. S.; Tu, H.; Ursu, S.; Walker, N.; Yan, X.; Ye, Q.; Powers, J. P.
Bioorg. Med. Chem. Lett. 2008, 18, 3513.
In summary, significant improvement in both potency and PK
property was achieved by a series of modifications starting from
1. Modification of the sulfonamide aryl substitution led to the dis-
covery of the trifluoromethylcarbinol group, resulting in a three-
fold improvement in biochemical and cellular potency over the
corresponding tert-butyl analog. Further modifications to the N-
aryl substituents led to the discovery of a 1, 1-cyclopropyl spacer,
producing a fourfold improvement in biochemical potency over the
corresponding methylene compound. The hERG pharmacophore
model was successfully used to reduce hERG potency. In addition,
combination of the features resulted in a potent, selective, and or-
ally bioavailable compound (S)-28, which demonstrated 11b-HSD1
inhibition in a cynomolgus monkey ex vivo model. Finally, X-ray
co-crystallographic data of (S)-28 with 11b-HSD1 revealed the
key interactions for the inhibitor binding.
15. Tu, H.; Powers, J. P.; Liu, J.; Ursu, S.; Sudom, A.; Yan, X.; Xu, H.; Meininger, D.;
DeDraffenreid, M.; He, X.; Jaen, J. C.; Sun, D.; Labelle, M.; Yamamoto, H.; Shan,
B.; Walker, N.; Wang, Z. Bioorg. Med. Chem. 2008, 16, 8922.
16. All compounds gave satisfactory 1H NMR, HPLC, and MS data in full agreement
with their proposed structures and purity (>95%) was determined by HPLC
analysis.
References and notes
1. Draper, N.; Stewart, P. M. J. Endocrinol. 2005, 186, 251.
2. Thieringer, R.; Hermanowski-Vosatka, A. Expert Rev. Cardiovasc. Ther. 2005, 3,
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Walker, B. R.; Flier, J. S.; Mullins, J. J.; Seckl, J. R. Diabetes 2004, 53, 931.
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18. hERG modeling method:
A Unity hERG pharmacophore, developed from
literature data,19 was used to align this analog series. The model consists of
three hydrophobic (aliphatic as well as aromatic) groups and ionizable
nitrogen. This pharmacophore is similar to that published by Cavalli et al.20
In addition, we developed an anti-hERG feature consisted of a hydrogen bond
donor of specific location relative to the hERG ‘favorable’ features. The location
of the anti-hERG feature was derived from automatic molecular alignment of
an internal hERG dataset. In this data, potent hERG blockers where modified
with various types of hydrogen bond donors resulting in significant reduction
of hERG binding and patch clamp IC50. A Unity hydrogen bond donor feature
was build based on this alignment and combined with the hERG
pharmacophore.
5. Seckl, J. S.; Walker, B. R. Endocrinology 2001, 142, 1371.
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M.; Koo, G. C.; Grand, C. B. L.; Li, Z.; Metzger, J. M.; Mundt, S. S.; Noonan, H.;
Nunes, C. N.; Olson, S. H.; Pikounis, B.; Ren, N.; Robertson, N.; Schaeffer, J. M.;
Shah, K.; Springer, M. S.; Strack, A. M.; Strowski, M.; Wu, K.; Wu, T.; Xiao, J.;
Zhang, B. B.; Wright, S. D.; Thieringer, R. J. Exp. Med. 2005, 202, 517.
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Vosatka, A.; LeGrand, C. B.; Mundt, S. S.; Robbins, M. A.; Schaeffer, J. M.;
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19. Sybyl, version 7.0; Tripos, Inc.: St. Louis, MO, 2003.
20. Cavalli, A.; Poluzzi, E.; De Ponti, F.; Recanatini, M. J. Med. Chem. 2002, 45, 3844.
21. The atomic coordinate has been deposited in the Protein Data Bank under an
accession code 3D4N.