Nitrogen-appended N-alkylsulfonamides as inhibitors of γ-secretase

Article abstract of DOI:10.1016/j.bmcl.2007.10.105

The synthesis and γ-secretase inhibition data for a series of nitrogen-appended N-alkylsulfonamides (11-47) are described. Inhibition of brain Aβ in transgenic mice was demonstrated by two of these compounds (23 and 44).

Full text of DOI:10.1016/j.bmcl.2007.10.105

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 175–178
Nitrogen-appended N-alkylsulfonamides as inhibitors of c-secretase
Carl P. Bergstrom,a,* Charles P. Sloan,a Henry H. Wang,a Michael F. Parker,a
David W. Smith,a Ming Zheng,b Steven B. Hansel,b,ꢀ Craig T. Polson,c Lauren E. Barber,c
Isia Bursuker,c Valerie L. Guss,c Jason A. Corsa,c Donna M. Barten,c
Kevin M. Felsensteinc,ꢁ and Susan B. Robertsc
aDepartment of Discovery Chemistry, Research and Development, Bristol-Myers Squibb, 5 Research Parkway,
Wallingford, CT 06492, USA
bDepartment of Drug Metabolism and Pharmacokinetics, Research and Development, Bristol-Myers Squibb,
5 Research Parkway, Wallingford, CT 06492, USA
cDepartment of Neuroscience Biology, Research and Development, Bristol-Myers Squibb, 5 Research Parkway,
Wallingford, CT 06492, USA
Received 11 September 2007; revised 25 October 2007; accepted 29 October 2007
Available online 1 November 2007
Abstract—The synthesis and c-secretase inhibition data for a series of nitrogen-appended N-alkylsulfonamides (11–47) are
described. Inhibition of brain Ab in transgenic mice was demonstrated by two of these compounds (23 and 44).
Ó 2007 Elsevier Ltd. All rights reserved.
Alzheimer’s disease (AD) is a progressive dementing
neurodegenerative disorder characterized pathologically
by the presence of plaques composed of the 40–42 amino
acid peptide amyloid-b (Ab) and by increased levels of
soluble oligomeric Ab.1 The actions of both b- and
c-secretases are responsible for the cleavage of b-amy-
loid precursor protein (APP) to release Ab peptides.2
Human genetics suggests a link between elevated levels
of Ab42 and early-onset familial AD.3 Furthermore, sol-
uble oligomeric Ab has been shown to be neurotoxic
in vitro.4 Structurally diverse small molecule inhibitors
of c-secretase have been described in the literature.5
For these reasons, we have targeted the inhibition of
c-secretase, as one of the proteases responsible for the
unfavorable cleavage of APP, as a therapeutic approach
to treat the underlying pathology of AD.
using a cell-based assay.7 Compound 1 provided an
attractive lead and subsequent analogs such as 2 exhib-
ited more potent inhibition of c-secretase (Fig. 1). Com-
pound 2 was selected for oral administration in Tg2576
bAPP-Swedish transgenic mice at a single 500 lmol/kg
dose.8 Three hours after dosing, a 25% reduction in
brain Ab was observed. This modest reduction in brain
Ab, despite achieving robust brain concentrations, sug-
gested that we needed to design even more potent inhib-
itors of c-secretase.
Toward this end, we decided to further examine the role
of the hydrophobic 2-pentyl sidechain by synthesizing a
series of nitrogen-appended analogs of N-alkylsulfona-
mide 2. Herein we report the SAR of this series of
c-secretase inhibitors.
In a previous communication,6 we described the identi-
OH
OH
fication of screening hit 1, an inhibitor of c-secretase,
Keywords: Alzheimer’s disease; c-Secretase; Aryl sulfonamides.
Cl
N
Cl
Cl
N
*
Corresponding author. Tel.: +1 2036776295; fax: +1 2036777702;
e-mail: carl.bergstrom@bms.com
S
O
S O
O
Cl
O
ꢀ
Present address: Pfizer Inc., 2800 Plymouth Road, Ann Arbor, MI
48105, USA.
1: Aβ40 IC50 = 850 nM
2 : Aβ40 IC50 = 5 nM
ꢁ
Present address: Johnson and Johnson PRD, Spring House, PA
19477, USA.
Figure 1.
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.10.105

176
C. P. Bergstrom et al. / Bioorg. Med. Chem. Lett. 18 (2008) 175–178
Table 1. c-Secretase inhibition for amides 11–21
We targeted alkyl bromide 9 and primary amine 10 as
versatile intermediates for the synthesis of nitrogen-ap-
pended N-alkylsulfonamides. A convergent approach
for the synthesis of these intermediates is shown in
Scheme 1. The key strategic feature of this approach
involves a Mitsunobu9 coupling of arylsulfonamide 6
OH
Cl
Cl
N
S
O
O
O
and
(S)-5-[[dimethyl(1,1-dimethylethyl)-silyl]oxy]-2-penta-
HN
nol.10 The resulting silyl ether 7 was deprotected with
TBAF to produce alcohol 8, which was converted to pri-
mary amine 10 using a standard three-step procedure.
R3
Ab40
IC50
Ab40
11
IC50
O
O
11
Primary amine 10 was acylated using array synthesis to
determine if heteroatoms would be tolerated at the ter-
minus of the 2-pentyl sidechain and to investigate the
steric requirements of this sidechain for c-secretase inhi-
bition. The steric requirements did not appear to be
stringent as formamide 11 was nearly equipotent to
mandelamides 19 and 20 as shown in Table 1. Overall
this group of amides did not achieve a significant in-
crease in potency compared to previous lead 2.
Compound
Compound
HN
HN
R3
(nM)
(nM)
R3
O
O
HN
11
5.1
17
15
HN
H
O
O
It is worth noting that the added hydroxyl group of the
mandelamides 19 and 20 resulted in roughly an order of
magnitude greater potency as compared to phenylacet-
amide 18. For this reason, we synthesized a small group
of sulfonamides from bromo intermediate 9 (Scheme 2)
to determine if a sulfonamido moiety would be a reason-
able isostere for the mandelamide. Benzenesulfonamide
25 was found to have similar potency to mandelamides
19 and 20, suggesting that these terminal moieties inter-
act with c-secretase in a similar fashion. Methyl sulfon-
amide 22 was the first compound in this series to exhibit
O
O
HN
HN
12
13
7.3
13
18
19
26
HN
HN
1.6
HO
O
O
O
HN
HO
14
8.1
20
2.9
HN
OH
OH
CO2Me
NH
S O
O
CO2Me
NH2
b
c
a
Cl
Cl
Cl
Cl
NH
S O
O
HN
O
O
HN
HN
15
16
6.9
21
72
3
O
Cl
5
4
OTHP
OTHP
N
S O
O
OTHP
d
f
Cl
Cl
NH
S O
O
Cl
Cl
Cl
Cl
N
S O
O
14
OR1
Br
9
6
7 : R1 = TBS
8 : R1 = H
e
j
R2 = THP
OR2
picomolar potency as shown in Table 2. In fact, 22 was
an order of magnitude more potent than 2. Further-
more, the N-methyl analog 23 was nearly equipotent
to 22, demonstrating that the sulfonamide hydrogen of
22 was not critical for inhibition of c-secretase. In fur-
ther studies, compound 23 was selected for oral admin-
istration in Tg2576 bAPP-Swedish transgenic mice at a
single 200 lmol/kg dose. Three hours after dosing, a
27% reduction in brain Ab was observed. The plasma le-
vel of this compound was 12,302 11,323 nM and
the brain level was 759 459 nM. This represents a sim-
ilar reduction in brain Ab at less than one-half the dose
of 2.
OTHP
N
11-21 : R2 = H
g, h
i
Cl
Cl
Cl
N
S O
O
O
S O
NH2
HN
O
R3
10
Cl
Scheme 1. Reagents and conditions: (a) p-ClPhSO2Cl, pyr, CH2Cl2, rt,
8 h, 91%; (b) LiAlH4, THF, 0 °C, 4 h, 77%; (c) DHP, PPTS, CH2Cl2,
rt, 6 h, 98%; (d) (S)-5-[[dimethyl(1,1-dimethylethyl)-silyl]oxy]-2-penta-
nol10, DIAD, PPh3, THF, rt, 16 h, 64%; (e) TBAF, THF, rt, 3 h, 96%;
(f) CBr4, PPh3, CH2Cl2, rt, 8 h, 62%; (g) NaN3, K2CO3, DMF, rt, 6 h,
83%; (h) H2 (1 atm), 10% Pd–C, EtOAc, rt, 8 h, 86%; (i) R3C(O)Cl,
pyr, CH2Cl2, rt, 8 h; (j) 1 M HCl, THF, rt, 6 h.

C. P. Bergstrom et al. / Bioorg. Med. Chem. Lett. 18 (2008) 175–178
177
Table 3. c-Secretase inhibition for amines 26–34
OH
OTHP
N
S O
O
a, b
OH
Cl
Cl
N
S O
O
Cl
Cl
SO2R5
22-25
N
Br
R4
Cl
Cl
N
9
S
O
O
NR6R7
OH
N
S O
O
OTHP
c, d
Ab40
IC50
(nM)
Ab40
11
IC50
Cl
Cl
Cl
Cl
N
S O
O
11
Compound
Compound
NR6R7
NR6R7
NR6R7
(nM)
Br
9
26-47
N
Scheme 2. Reagents and conditions: (a) HN(R4)SO2R5, NaH, DMF,
60 °C, 8 h; (b) 1 M HCl, THF, rt, 6 h; (c) HNR6R7, K2CO3, DMF, rt,
18 h; (d) 1 M HCl, THF, rt, 6 h.
26
288
262
6.5
31
50
3.1
29
84
NH2
N
27
28
32
33
34
HN
Table 2. c-Secretase inhibition for sulfonamides 22–25
O
OH
N
N
N
Cl
Cl
N
N
S O
O
SO2R5
N
R4
29
30
29
36
HN
HN
O
11
Ab40 IC50 (nM)
Compound
SO2R5
N
R4
O
S
22
23
24
0.23
0.32
1.1
HN
O
A set of nitrogen based heterocyclic derivatives, includ-
ing pyrazoles, imidazoles, and triazoles, exhibited bet-
ter potency than their amino analogs 26–34 as shown
in Table 4. Some of the most promising of these het-
erocycles were the tetrazole analogs, with 44, 45, and
47 possessing subnanomolar potency. Compound 44
was selected for oral administration in Tg2576 mice
at a single 200 lmol/kg dose. Three hours after dosing,
a 41% reduction in brain Ab was observed. The plasma
level of this compound was 5473 1083 nM and the
brain level was 1155 279 nM. Tetrazole 44 shows
an improved brain Ab lowering activity and an im-
proved brain-to-plasma ratio compared to methyl sul-
fonamide 23.
O
S
N
N
O
O
O
S
O
S O
HN
25
7.4
In summary, we have described the SAR for a series of
nitrogen-appended analogs of sulfonamide 2. Hetero-
atom substitution is clearly preferred at the terminus
of the 2-pentyl sidechain as compounds 22, 23, 44, and
47 are roughly an order of magnitude more potent than
2. Furthermore, compounds 23 and 44 were more effec-
tive than compound 2 in reducing brain Ab in transgenic
mice. Subsequent communications will describe our con-
tinued efforts to design analogs with improved in vivo
profiles.
In an effort to design a compound with improved brain
levels compared to methyl sulfonamide 23, we decided
to synthesize (Scheme 2) a set of amines and heterocy-
cles at the terminus of the 2-pentyl sidechain. Table 3
shows that the majority of the resulting amino
compounds exhibited reduced potency as compared to
des-amino compound 2, although dimethylamino
compound 28 and morpholino compound 32 were
essentially equipotent to 2.

178
C. P. Bergstrom et al. / Bioorg. Med. Chem. Lett. 18 (2008) 175–178
Table 4. c-Secretase inhibition for heterocycles 35–47
References and notes
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Drug. Discov. Devel. 2001, 4, 390; (b) Walsh, D. M.;
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3363; (b) Schmidt, B.; Baumann, S.; Braun, H. A.; Larbig,
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OH
Cl
Cl
N
S O
O
NR6R7
Ab40
IC50
(nM)
Ab40
11
IC50
11
Compound
Compound
NR6R7
NR6R7
(nM)
N
N
N
35
18
42
61
N
N
N
N
Ph
6. Parker, M. F.; Barten, D. M.; Bergstrom, C. P.; Bronson,
J. J.; Corsa, J. A.; Deshpande, M. S.; Felsenstein, K. M.;
Guss, V. L.; Johnson, G.; Keavy, D. J.; Lau, W. Y.; Loo,
A.; Mock, J.; Polson, C. T.; Sloan, C. P.; Wallace, O. B.;
Wang, H. H.; Williams, A. Bioorg. Med. Chem. Lett. 2007,
17, 4432.
N
N
N
36
37
38
39
40
41
11
43
44
45
46
47
5.6
N
N
NMe2
7. H4 human neuroglioma cells expressing HPLAPÆ-
bAPP164SFAD were grown in high glucose (4.5 g/L)
DMEM (Invitrogen) media supplemented with 10%
FBS, 100 lg/mL pen-strep, 2 mM glutamine, and 100 lg/
mL geneticin. Cells were aliquoted into a 96-well plate, and
after attachment the medium was replaced with Ultracul-
ture (Whittaker Bioproducts) containing individual
compounds of interest (final DMSO concentration of 1%).
After an overnight incubation, the conditioned medium was
removed and evaluated for the presence of Ab in a sandwich
ELISA using a monoclonal C-terminal Ab40 specific
capture antibody and an HRP labeled monoclonal antibody
to the N-terminus of Ab for detection. The endpoint
measurement of Ab1–40 level was developed using TMB
reagent followed by the addition of 1 M phosphoric acid.
The plates were read at 450 nm.
N
N
12
0.51
0.75
15
N
N
N
N
N
N
N
N
N
N
N
0.9
4.8
1.2
6.1
N
N
N
N
Ph
N
N
N
N
N
N
N
N
8. Barten, D. M.; Guss, V. L.; Corsa, J. A.; Loo, A.; Hansel,
S. B.; Zheng, M.; Munoz, B.; Srinivasan, K.; Wang, B.;
Robertson, B. J.; Polson, C. T.; Wang, J.; Roberts, S. B.;
Hendrick, J. P.; Anderson, J. J.; Loy, J. K.; Denton, R.;
Verdoorn, T. A.; Smith, D. W.; Felsenstein, K. M. J.
Pharmacol. Exp. Ther. 2005, 312, 635.
N
N
NMe2
N
N
0.53
N
9. Mitsunobu, O. Synthesis 1981, 1.
N
N
10. (S)-5-[[Dimethyl(1,1-dimethylethyl)-silyl]oxy]-2-pentanol
was synthesized via the following procedure: commercially
available (S)-1,4-pentanediol (2.86 g, 27.5 mmol) was
stirred with TBSCl (4.55 g, 30.2 mmol), TEA (4.59 mL,
33.0 mmol), and DMAP (0.335 g, 2.75 mmol) in CH2Cl2
(55 mL) at 0 °C for 4 h. The resulting mixture was
concentrated and purified by silica gel column chroma-
tography eluting with 4:1 hexanes/ethyl acetate to isolate
the title compound in 86% yield.
N
Acknowledgments
11. IC50s were determined using a cell-based assay (see Ref. 6).
Values are means of two experiments, with 12 drug
concentrations in each experiment; intra-assay variance
was <10%.
The authors would like to thank Drs. Richard E. Olson,
Robert Gentles, and Michael A. Poss for their helpful
comments.