Discovery of a novel [3.2.1] benzo fused bicyclic sulfonamide-pyrazoles as potent, selective and efficacious γ-secretase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.12.039

Structure-activity relationship (SAR) of a novel, potent and metabolically stable series of benzo [3.2.1] bicyclic sulfonamide-pyrazoles as γ-secretase inhibitors are described. Compounds that are efficacious in reducing the cortical Aβx-40 levels in FVB mice via oral dose, as well as those with high selectivity over Notch, are highlighted.

Full text of DOI:10.1016/j.bmcl.2012.12.039

Bioorganic & Medicinal Chemistry Letters xxx (2013) xxx–xxx
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of a novel [3.2.1] benzo fused bicyclic sulfonamide-
pyrazoles as potent, selective and efficacious c-secretase inhibitors
a
a,
Xiaocong M. Ye a, , Andrei W. Konradi , Minghua Sun , Shendong Yuan a, Danielle L. Aubele a,
Michael Dappen a, Darren Dressen a, Albert W. Garofalo a, Jacek J. Jagodzinski a, Lee Latimer a,
Gary D. Probst a, Hing L. Sham a, David Wone a, Ying-zi Xu a, Daniel Ness b, Elizabeth Brigham b,
Grace T. Kwong b, Chris Willtis b, George Tonn c, Erich Goldbach c, Kevin P. Quinn c, Hongbin H. Zhang c,
John-Michael Sauer c, Michael Bova d, Guriqbal S. Basi e,à
⇑
a Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Blvd., South San Francisco, CA 94080, United States
b Department of Pharmacology, Elan Pharmaceuticals, 180 Oyster Point Blvd., South San Francisco, CA 94080, United States
c Department of Drug Metabolism and Pharmacokinetics, Elan Pharmaceuticals, 180 Oyster Point Blvd., South San Francisco, CA 94080, United States
d Department of Assay Development, Elan Pharmaceuticals, 180 Oyster Point Blvd., South San Francisco, CA 94080, United States
e Department of Biology, Elan Pharmaceuticals, 180 Oyster Point Blvd., South San Francisco, CA 94080, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Structure–activity relationship (SAR) of a novel, potent and metabolically stable series of benzo [3.2.1]
Received 3 October 2012
Revised 10 December 2012
Accepted 13 December 2012
Available online xxxx
bicyclic sulfonamide-pyrazoles as c-secretase inhibitors are described. Compounds that are efficacious
in reducing the cortical Abx-40 levels in FVB mice via oral dose, as well as those with high selectivity over
Notch, are highlighted.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Alzheimer’s disease
Amyloid precursor protein
c
c
-Secretase
-Secretase inhibitor
Notch
Alzheimer’s disease (AD) is the third most common cause of
itors (GSIs), with improved selectivity for APP, high potency
in vitro, suitable pharmacokinetics, and oral activity in rodents.
In several previous communications, we have reported very po-
tent GSIs featuring sulfonamides and pyrazoles.9,10 Two such GSIs,
1 and 2, illustrated in Figure 1, are exceptionally selective for APP
over Notch, measured using either biochemical11 or cellular12
assays.
Unfortunately, both 1 and 2 were metabolically unstable in
microsomes and therefore not suitable for further development.
Thus, we initiated an effort to identify related compounds with re-
duced oxidative metabolism. Studying the available SAR, we
hypothesized the 3-fluorophenyl group in 1 and the phenyl group
in 2 may contribute to the high APP selectivities of these two com-
pounds. Based on this hypothesis, we imagined the benzo [3.2.1]
bicycle 3, illustrated in Figure 1, should maintain the high selectiv-
ity of 1 and 2, but have greater oxidative metabolic stability due to
hindrance of its saturated carbon atoms. We developed the syn-
thetic approach illustrated in Scheme 1 to prepare a series of benzo
[3.2.1] bicycles. The key intermediate 7 was formed in good yield
using a hetero-Diels–Alder reaction. After pyrazole formation,
death, and the most common neurodegenerative disease, in the
developed world.1 The pathological hallmarks of AD are extracellu-
lar senile plaques, containing aggregated amyloid-b peptides (Ab),
and intracellular neurofibrillary tangles, containing hyper-phos-
phorylated tau. Ab is a 36–43 aminoacid peptide generated by
sequential cleavage of amyloid precursor protein (APP) by the pro-
teases BACE and
are being explored by several research teams, towards identifying
potential treatments for AD.4,5
-Secretase cleaves several non-APP
c
-secretase.2,3 Inhibitors of these two proteases
c
substrates, including Notch, and inhibition of Notch cleavage leads
to toxicity in peripheral organs.6–8 Therefore, compounds selective
for inhibition of APP cleavage over Notch cleavage are desirable.
Herein we describe a new class of APP-selective c-secretase inhib-
⇑
Corresponding author.
E-mail address: mxcye@hotmail.com (X.M. Ye).
Present address: Genentech, 1 DNA Way, MS-18B, South San Francisco, CA, United
States.
Present address: Neotope, 650 Gateway Blvd., South San Francisco, CA 94080,
United States.
à
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.12.039
Please cite this article in press as: Ye, X. M.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2012.12.039

2
X. M. Ye et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
Cl
F
O
γ
γ
APP IC50 = 8.3 nM
S
N
O
Notch IC50 = 662 nM
Notch/APP (enz) = 80
SNC cell ED50 = 47.1 nM
γ
SNC Notch IC50 = 11397 nM
F3C
Notch/APP (cell) = 242
N
NH
O
1
S
O
N
F3C
O
S
N
NH
O
γ
APP IC50 = 14 nM
3
SNC cell ED50 = 40 nM
N
γ
SNC Notch IC50 = 10932 nM
Notch/APP (cell) = 276
N
NH
2
Figure 1. Sulfonamide-pyrazole GSIs with exceptional APP/Notch selectivity.
R2
R1
O
S
N
R1
O
N
O
R1
S
X
CHO
Br
SO2NH2
a
b
O
R2
X
Br
X
R2
Br
4
5
6
7
O
R1
R2
R2
X
R1
O
S
N
O
S
O
X
O
c, d
e
N
N
Br
N
HN
NH
8
3
Scheme 1. Reagents and conditions: (a) TiCl4, Et3N, DCM, THF; (b) Danishefsky’s diene [(E)-1-methoxy-3-trimethylsilyloxy-1,3-butadiene], PhMe; (c) Bredereck’s reagent
[tert-butoxy-bis(dimethylamino)-methane]; (d) hydrazine monohydrate, EtOH; (e) nBu3SnH, AIBN, PhH.
Table 1
Sulfonamide substitution SAR
F
O
Ar
S
O
N
N
NH
a
Compound
Ar
c
-APP IC50 (nM)
c
-Notch
Notch/APP
ratio (enzy)
SNC cellular
ED50 (nM)
SNC cellular Notch
IC50 (nM)
Notch/APP
ratio (cell)
Note
a
a
a
IC50 (nM)
3a
3aa
3b
3c
3d
3e
3f
3g
3h
3i
4-CF3Ph
4-CF3Ph
2-CF3-5-Pyridyle
5-CF3-Pyridyle
5-Cl-Thiophenyl
3,4-diFPh
0.4
674
0.4
N/A
N/A
N/A
N/A
N/A
N/A
N/A
36
30,305
18
N/A
N/A
N/A
N/A
N/A
N/A
N/A
90
45
45
2.2
2474
1
6.4
4.7
2.5
3.3
43.8
33.1
7.1
250
>40,000
146
622
497
467
826
4101
3346
971
114
Single ent.
Inactive ent. of 7a
Single ent.
Single ent.
Single ent.
Single ent.
Single ent.
Single ent.
Single ent.
Single ent.
146
97
106
187
250
94
4-F
2,4-diClPh
4-CF2HOPh
4-CF3OPh
101
137
a
Values are means of three experiments.
reductive cyclization by a radical process formed the final prod-
ucts. The enantiomers of the final products were separated by chi-
ral HPLC. In all cases, the separated enantiomers have very
different bioactivities (see 3a and 3aa in Table 1), and the
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X. M. Ye et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
3
F
F3C
N
F3C
N
N
N
F3C
N
S
N
N
O
O
O
N
S
O
S
O
S
O
N
N
N
N
NH
NH
N
NH
γ
γ
APP IC50 = 47 nM
OxMet = N/A
GluMet = N/A
APP IC50 = 133 nM
γ
APP IC50 = 9.4 nM
OxMet = 83
GluMet = N/A
OxMet = 42
GluMet = N/A
Figure 2. Heteroaromatic replacements for the benzo group.
125
100
75
50
25
0
fonamide-pyrazole GSIs, 4-substituted benzene-sulfonamides are
generally preferred. 5-Cl-thiophene-sulfonamides have potency
comparable to 4-substituted benzene-sulfonamides, but the former
are less stable to oxidative metabolism. Overall, 4-trifluoro-
methyl-benzenesulfonamides and 2-trifluoromethyl-5-pyridine-
sulfonamides exhibited the best in vitro potencies.
Substituents on the benzo group were explored next. Com-
pounds with chlorine substitution on C-5 (3k) or C-6 (3l) were
more potent than the analog with hydrogen atoms at both of these
positions (3j). Chlorine on C-5 affords slightly higher potency than
chlorine on C-6. Chlorine substitution on C-7 (3m) has little effect
on potency, but chlorine substitution on C-8 (3n) leads to a more
than 60-fold decrease in potency.
Fluorine substitution on C-5 (3a) maintained the potency of
chlorine substitution on C-5 (3k). Surprisingly, fluorine substitu-
tion on C-8 (3o) did not reduce potency as did chlorine substitution
on C-8 (3n). Two di-fluoro compounds (3p, 3q) were prepared, and
both displayed excellent potencies. Compounds substituted with
cyclopropyl (3r), trifluoromethyl (3t, 3u) and 4-fluorophenyl (3s)
were significantly less potent than the chlorine and fluorine substi-
tuted analogs.
Brain Aβ 3 mg/kg
Brain Aβ 10 mg/kg
25% Reduction
0
3
6
9
12
24
Time (Hours)
Figure 3. Reduction of cortical Abx-40 in FVB mice following single oral doses of 3a.
configurations reported here are assigned by referring to SAR
among earlier sulfonamide-pyrazole GSIs, for which small mole-
cule X-ray structures are available.9,13
Using a synthetic route similar to that illustrated in Scheme 1,
several compounds with heteroaromatic rings in place of the benzo
Substituents on the sulfonamide aryl ring were studied first,
and the results are listed in Table 1. As observed with earlier sul-
Table 2
Benzo substitution SAR
1"
X
R
6
F3C
7
6"
5
4
O
3"
S
O
4"
N
9
10
3
1 N
NH
2
Compound
X
R
c
-APP
c
-Notch
Notch/APP
ratio (enzy)
SNC cellular
ED50 (nM)
SNC cellular Notch
IC50 (nM)
Notch/APP
ratio (cell)
Note
a
a
a
a
IC50 (nM)
IC50 (nM)
3j
3k
3l
CH
CH
CH
CH
CH
CH
N
N
N
CH
N
N
H
5-Cl
6-Cl
7-Cl
8-CL
5-F
5-F
1.9
117
14
45
165
6998
36
18
49
12
127
190
2827
N/A
N/A
62
64
79
89
57
90
45
49
40
115
41
46
4.2
0.93
2.1
14.2
844
2.2
1
4.2
1.6
8
595
113.33
268
1831
>40,000
250
146
522
158
1093
5621
>40,000
>40,000
8043
142
122
128
129
Single ent.
Single ent.
Single ent.
Single ent.
Single ent.
Single ent.
Single ent.
Single ent.
Single ent.
Single ent.
Single ent.
Single ent.
Single ent.
Single ent.
0.22
0.57
1.86
122
0.4
0.4
1
0.3
1.1
3m
3n
3a
3b
3o
3p
3q
3r
114
146
124
99
137
89
8-F
5,8-diF
6,7-diF
5-cPr
5-(40-FPh)
6-CF3
7-CF3
4.6
63.5
364
1236
58
3s
3t
3u
60.9
N/A
N/A
CH
CH
139
a
Values are means of three experiments.
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X. M. Ye et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
Table 3
In vitro DMPK properties of selected compounds
a
Compound
c
-APP IC50 (nM)
Glucuron. microsom. % remainb (h, d, r, m)
Oxidative metabol % remainc (h, d, r, m)
Papp (nm/s)
Pgp efflux
Sol (lM)
3a
3b
3j
0.4
0.4
1.9
100, 79, 45, 53
100, 88, 71, 100
75, 85, 77, 87
77, 78, 33, 53
65, 66, 37, 46
47, 57, 27, 53
158
172
193
0.8
1.5
1.1
65
100
15
a
Values are means of three experiments.
b
Percentage of compound (2 lM) remaining after 30 min incubation in liver microsomes (0.5 mg protein) supplemented with 1 mM UDPGA, 100 mM MgCl2, and 25 mg/
mL alamethacin at 37 °C in phosphate buffer.
c
Percentage of compound (1 lM) remaining after 30 min incubation in liver microsomes (0.5 mg protein) supplemented with 1 mM NADPH at 37 °C in phosphate buffer.
Table 4
Summary of cross species in vivo PK parameters of 3a
Parameter
SD rat
Beagle dog
Cynomolgus monkey
CL (L/h/kg)
Vss (L/kg)
AUC0–inf. (ng h/mL)
%F
2.9
3.5
346
17a
0.8
1.8
0.7
2.5
1324
1430
26a
16b
a
%F values based on a 2 mg/kg oral administration.
%F value based on a 1 mg/kg oral administration.
b
group in 3 were prepared (Fig. 2). All of these compounds are po-
tent GSIs, but the five-membered heteroaromatics are less potent
than the six-membered heteroaromatics.
Several examples of the new GSIs described in this Letter have
fair in vitro DMPK properties as illustrated in Table 3.
Encouraged by 3a’s favorable in vitro properties, we studied the
pharmacokinetics in multiple species. Consistent with the in vitro
properties, 3a exhibited moderate to high clearance in rat and
moderate clearance in dog and monkey. The bioavailability ranged
between 16% and 25% across species (Table 4).
Figure 5. PK-PD in FVB mice: effects of 3a on Ab protein in cortex and Hes1 mRNA
in thymus 3 h post dose.
Compound 3a was tested for bioactivity in FVB mice. As illus-
trated in Figure 3, 3 h after a single 3 mg/kg dose of 3a, the cortical
Abx-40 level was reduced by 30%, and the Ab level returned to
baseline within 24 h. Six hours after a single 10 mg/kg dose of
3a, the cortical Abx-40 level was reduced by 60%, and the Ab level
returned to baseline within 24 h. The brain to plasma exposure ra-
tios of this compound ranged from 0.9 to 1.1.
It is interesting to compare the biochemical and cellular APP/
Notch selectivities of 3a (Table 2) with those of three previously re-
ported sulfonamide GSIs, BMS-708163,14,15 GSI-953,16 and
ELND00617 (Fig. 4). Tested side by side, 3a is 6- to 14-fold more
selective than any of these compounds in our biochemical assay,
and 1.5- to 2.5-fold more selective than any of these compounds in
our cellular assay. We do not have a hypothesis for non-correlation
of biochemical and cellular selectivities, but this has been a
reproducible finding in our hands.
Earlier, we reported for ELND006 a Hes1 mRNA biomarker can
be used to determine an acute in vivo APP/Notch selectivity.17a In
that study, the plasma concentration of ELND006 required for a
25% reduction of cortical Ab was 57-fold lower than that required
for a 25% reduction of Hes1 mRNA in thymus. We have tested 3a in
a similar PK-PD experiment, in which FVB mice were treated with
0.3, 1, 3, 10, 100 or 300 mg/kg 3a, followed by quantifying 3a in
plasma, Ab in cortex, and Hes1 mRNA in thymus. As illustrated in
Figure 5, 3a requires a 92-fold lower plasma concentration for a
25% reduction of Ab than for a 25% reduction of Hes1 mRNA. The
slightly higher in vivo selectivity of 3a, compared to ELND006, cor-
relates more closely to the slightly higher cellular selectivity of 3a,
than to the significantly higher enzyme selectivity of 3a.
In summary, we designed and prepared a novel series of potent
and APP/Notch selective sulfonamide-pyrazole GSIs, featuring a
CF3
F3C
O
O
N
O
S
N
H2N
S
Cl
O
O
HO
F3C
O
S
F
F
O
O
N
S
H
Cl
N
CF3
F
N
NH
N
BMS-708163
GSI-953
ELND006
γ
γ
γ
γ
γ
γ
APP IC50 = 0.13 nM
Notch IC50 = 1.5 nM
APP IC50 = 1.6 nM
APP IC50 = 0.34 nM
Notch IC50 = 5.3 nM
Notch IC50 = 10.5 nM
Notch/APP (enz) = 12
Notch/APP (enz) = 6.6
Notch/APP (enz) = 16
SNC cell ED50 = 1.2 nM
SNC cell ED50 = 7.8 nM
SNC cell ED50 = 1.1 nM
γ
γ
γ
SNC Notch IC50 = 71 nM
SNC Notch IC50 = 353 nM
SNC Notch IC50 = 82 nM
Notch/APP (cell) = 59
Notch/APP (cell) = 45
Notch/APP (cell) = 74
Figure 4. In vitro potencies and selectivities of BMS-708163, GSI-953, and ELND006.
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X. M. Ye et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
5
Goldbach, E.; Quinn, K. P.; Sauer, J.-M.; Brigham, E. F.; Wallace, W.; Nguyen, L.;
Hemphill, S. S.; Bova, M. P.; Basi, G. Bioorg. Med. Chem. Lett. 2009, 19, 4920.
12. Basi, G. S.; Hemphill, S.; Brigham, E. F.; Liao, A.; Aubele, D. L.; Baker, J.; Barbour,
R.; Bova, M.; Chen, X.-H.; Dappen, M. S.; Eichenbaum, T.; Goldbach, E.;
Hawkinson, J.; Lawler-Herbold, R.; Hu, K.; Hui, T.; Jagodzinski, J. J.; Keim, P. S.;
Miller, J. L., et al Alzheimers Res. Ther. 2010, 2, 36.
13. Mattson, M. N.; Neitzel, M. L.; Quincy, D. A.; Semko, C. M.; Garofalo, A. W.;
Keim, P. S.; Konradi, A. W.; Pleiss, M. A.; Sham, H. L.; Brigham, E. F.; Goldbach, E.
G.; Zhang, H.; Sauer, J.-M.; Basi, G. S. Bioorg. Med. Chem. Lett. 2010, 20, 2148.
14. Albright, C. F.; Dockens, R.; Olson, R. E.; Meredith, J. E.; Siemmon, R.; Lentz, K.
benzo [3.2.1] bicycle framework. The DMPK properties of current
scaffold were improved compared to the earlier series (exemplified
by compounds 1 and 2). The in vitro properties (i.e., suggestive to
good CNS penetration and moderate to good in vivo CL) were in
fact corroborated by in vivo cross species PK behaviors. The pres-
ence of a benzo group on the 3.2.1 bicycle framework may contrib-
ute to the enhanced APP/Notch selectivity, measured in vitro and
in vivo. Efforts to identify analogs with further improved stability
to oxidative metabolism will be reported in a subsequent Letter.
A.; Denton, R.; Pilcher, G.; Zaczek, R. In BMS-708163, a Potent and Selective c-
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Please cite this article in press as: Ye, X. M.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2012.12.039