N-(5-Chloro-2-(hydroxymethyl)-N-alkyl-arylsulfonamides as γ-secretase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2007.06.022

A series of N-alkylbenzenesulfonamides were developed from a high throughput screening hit. Classic and parallel synthesis strategies were employed to produce compounds with good in vitro and in vivo γ-secretase activity.

Full text of DOI:10.1016/j.bmcl.2007.06.022

Bioorganic & Medicinal Chemistry Letters 17 (2007) 4432–4436
N-(5-Chloro-2-(hydroxymethyl)-N-alkyl-arylsulfonamides
as c-secretase inhibitors
Michael F. Parker,a,* Donna M. Barten,b Carl P. Bergstrom,a Joanne J. Bronson,a
Jason A. Corsa,b Milind S. Deshpande,a, Kevin M. Felsenstein,b,à Valerie L. Guss,b
Steven B. Hansel,c Graham Johnson,a,§ Daniel J. Keavy,a Wai Y. Lau,a Jeremy Mock,a
C. V. C. Prasad,a Craig T. Polson,b Charles P. Sloan,a David W. Smith,a
Owen B. Wallace,a,– Henry H. Wang,a Andrew Williamsa and Ming Zhengc
aDepartment of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford,
CT 06492, USA
bDepartment of Neuroscience Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford,
CT 06492, USA
cDepartment of Drug Metabolism and Pharmacokinetics, Bristol-Myers Squibb Research and Development,
5 Research Parkway, Wallingford, CT 06492, USA
Received 2 May 2007; accepted 5 June 2007
Available online 10 June 2007
Abstract—A series of N-alkylbenzenesulfonamides were developed from a high throughput screening hit. Classic and parallel syn-
thesis strategies were employed to produce compounds with good in vitro and in vivo c-secretase activity.
Ó 2007 Elsevier Ltd. All rights reserved.
Alzheimer’s disease (AD) is a chronic, neurodegenera-
tive disorder with pathology characterized by the accu-
mulation of senile (neuritic) plaques, neurofibrillary
tangles, amyloid deposition in neural tissues and vessels,
synaptic loss, and neuronal death.1a,b,2 Evidence sug-
gests the accumulation of Ab peptides is responsible
for the neuronal toxicity that is associated with AD.3
Ab peptides are generated by sequential proteolytic
cleavage of a 695–770 amino acid b-amyloid precursor
protein (b-APP)4 by the action of both b and c-secreta-
ses, leading to elevated levels of Ab peptides. We have
been engaged in the identification of small molecules
that inhibit the production of b-amyloid peptide (Ab)
from b-APP, particularly via inhibition of the cleavage
mediated by c-secretase. This approach has potential
to provide a therapy that would prevent the progression
of AD by the inhibition of Ab production.5
A cell-based assay measuring Ab production6 was per-
formed on our internal compound collection and the
3-chloro-2-hydroxymethy-benzenesulfonamide deriva-
tive 17 (Fig. 1) was found to be a modest inhibitor of
c-secretase (IC50 = 850 nM). A cell free assay that
specifically detects c-secretase cleavage of membrane
bound precursors was used to profile select compounds
from this screen.8,9 These compounds exhibited a profile
consistent with the inhibition of c-secretase. Herein, we
report the SAR within this series of substituted benzene
sulfonamides c-Secretase inhibitors.
Keywords: c-Secretase; Alzheimers; N-alkyl-arylsulfonamides.
*
Corresponding author. Tel.: +1 203 677 6466; fax: +1 203 677
7702; e-mail: parkerm@BMS.com
OH
Present address: Achillion Pharmaceuticals Inc., New Haven CT
06511, USA.
Cl
N
S
à
§
Present address: Johnson and Johnson PRD, Spring House, PA
19477, USA.
O
O
1
Cl
Present address: Rib-X Pharmaceuticals, New Haven CT
06511,USA.
Present address: Eli Lilly, Indianapolis, IN 46285, USA.
–
Figure 1.
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.06.022

M. F. Parker et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4432–4436
4433
Table 1. Modification of R1 in the 4-MePh sulfonamide series
The key intermediate 5-chloro-2-((tetrahydro-2H-pyran-
2-yloxy) methyl) aniline 3 was prepared from the com-
mercially available (4-chloro-2-nitrophenyl) methanol 2
by protection of the alcohol and reduction of the nitro
group. Aniline 3 was elaborated to various sulfonamides
by acylation with an array of sulfonyl chlorides.
OH
R1
Cl
N
O2S
CH3
The resulting sulfonamide 4 was amenable to Mitsun-
obu coupling with various alcohols or alkylation with
alkyl or benzyl halides to yield target molecules 5.
a
Exp. #
R1
Ab40 IC50 (nM)
Cl
1
850
OTHP
OH
NO2
OTHP
NH2
c
a,b
Cl
NH
O2S
Cl
Cl
6
7
1100
750
1300
400
700
2000
920
1000
40
2
3
4
R2
OH
R1
d,e
Or f,e
Cl
N
O2S
5
R2
aReagents: (a) 3,4-dihydro-2H-pyran, PPTS, DCM (62%) (b) Raney
nickel, H2, EtOH (98%) (c) R2- sulfonyl chloride, anhydrous pyridine,
00C, (d) triphenylphosphine, R1- OH, diisopropylazodicarboxylate,
THF (e)1N HCl, THF, 6H, (f) NaH, THF, R1-X.
8
9
Analogs of the initial screening hit 1 were accessible via
classic and parallel synthesis strategies. Our early focus
was on the exploration of the N-alkyl side chain. From
a moderate sized library of diverse compounds bearing
N-alkyl or N-alkylaryl substituents (Table 1), a few
key characteristics emerged. A variety of alkyl groups
conferred potency within twofold of the initial lead 1,
including the straight chain alkyls (e.g., 6–8), terminally
branched alkyls (e.g., 9–12), and cycloalkyls (e.g., 13).
The most interesting outcome from this set of com-
pounds was the significant enhancement in potency that
resulted from branching with an a-methyl group at the
point of attachment to the sulfonamide nitrogen. This
increase was found to be on average about 10-fold, as
in the case of 11/15 and 13/16. A more pronounced effect
was seen in the comparison of the n-butyl analogue 8
with the a-methyl butyl (2-pentyl) derivative 14, where
a 30-fold improvement in potency was realized. As can
be seen with example 17, this branching effect was lim-
ited to one carbon.
10
11
12
13
14
15
350
16
190
With the a-methyl butyl side chain fixed, a library fo-
cused on the sulfonamide aryl group was synthesized.
As shown in Table 2, this region of compound 1 was
quite sensitive to structural modification. The simple
unsubstituted benzene sulfonamide 18 was significantly
less potent than the 4-methyl derivative 9. However,
extension to larger 4-alkyl groups such as ethyl (19)
and isopropyl (20) resulted in diminished potency.
Transposition of the methyl group to the 3-position, as
in 21, also lead to significantly decreased potency
relative to 9. Within a series of 4-substituted phenyl
analogues, halogens were well tolerated, with the 4-
chlorophenyl compound 24 being most potent. Other
small electron-withdrawing groups were acceptable such
as trifluoromethyl (25) and nitrile (26). However, incor-
poration of an electron rich 4-methoxy group, as in 27,
was detrimental to potency. Inclusion of additional
chlorines on the 4-chlorophenyl group gave analogues
28–30 that were all less potent than the 4-chloro analog
24. Based on the potency of sulfonamide 24 (Ab40
17
1000
a Values are means of two experiments, with 12 drug concentrations in
each exp.; intra-assay variance <10%.
IC50 = 19 nM), the 4-chloro group appeared to be the
optimal substituent on the aryl sulfonamide portion of
the molecule.
Examples in Table 3 illustrate variation of the N-alkyl
substituent with the optimized 4-chlorosulfonamide sub-
stituent held constant. Simple unbranched alkyl ana-
logues 31 and 32 showed improved potency relative to
their 4-methylphenyl sulfonamide counterparts 6 and

4434
M. F. Parker et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4432–4436
Table 2. Modification of R2 in the N-(2-pentyl)sulfonamide series
Table 3. Modification of R1 in the 4-ClPh sulfonamide series
OH
R1
OH
Me
Cl
N
Cl
N
O2S
O2S
R2
R2
Ab40 IC50a (nM)
Cl
Exp. #
R1
Ab40 IC50 (nM)
a
Exp. #
18
1200
31
13
32
24
33
34
35
36
37
38
140
9
40
19
23
25
7
19
360
20
21
720
F
1200
F
49
12
14
22
23
24
66
56
19
F
Br
Cl
39
40
41
33
22
41
25
26
27
72
180
CF3
CN
Cl
1300
O
Cl
28
29
240
560
42
43
100
140
Cl
Cl
a Values are means of two experiments, with 12 drug concentrations in
each exp.; intra-assay variance <10%.
Cl
Cl
Cl
30
>25,000
8, respectively. A variety of a-methyl alkyl groups were
well tolerated as seen with examples 24 and 33–41. Com-
parison of the n-butyl analogue 32 with the 2-pentyl
derivative 24 illustrates the positive effect of branching
adjacent to the sulfonamide nitrogen, with the a-methyl
Cl
a Values are means of two experiments, with 12 drug concentrations in
each exp.; intra-assay variance <10%.

M. F. Parker et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4432–4436
4435
group giving a sevenfold increase in potency. The 5-flu-
oro-2-pentyl analogue 35 was particularly potent with
an IC50 of 7 nM. In the series of a-methyl cycloalkyl
derivatives 36–39, ring size played a role, with the cyc-
lobutyl 37 and the cyclopentyl 38 compounds having
the best potency. Unsaturated groups were also exam-
ined as in 40–43. Surprisingly, the alkene 43 was approx-
imately sevenfold less potent than its saturated
counterpart 24. Aromatic substituents were tolerated,
although phenyl groups (e.g., 40, 41) were preferred over
naphthyl 42. Our conclusion from this part of our SAR
study was that a-methyl branching was critical for good
potency and that a variety of alkyl groups gave reason-
able potency within a narrow range of IC50’s.
(R)-2-pentyl group with the 4-chlorophenyl sulfonamide
substituent provided 48, which proved to be one of the
most potent compounds to emerge from this series.
The 2-methyl-4-phenyl analogue 50 and the 2-hexyl
derivative 51 had similar potency to 48, while introduc-
tion of simple unsaturation in the side chain as in 49 re-
sulted in a threefold reduction in potency. This is similar
to the decrease in potency described for the alkene 43
compared with its saturated counterpart 24.
Analog 48 was evaluated in in vivo10 in Tg2576 bAPP-
Swedish transgenic mice at a single 500 lmol/kg dose.
Three hours after oral dosing, 48 produced a small,
non significant (25%) reduction in brain Ab, which
was associated with a 2- to 3-fold increase in b and a
cleaved C terminal fragments of APP. The plasma level
of this compound was 1.6 lM and the brain level was
5.2 lM. Subcutaneous dosing of 48 for 5 days BID did
lead to significant decreases in brain Ab of 38%, associ-
ated with plasma levels of 21 lM in plasma and 14 lM
in brain. The lack of robust efficacy in the in vivo model
may be due to plasma protein binding of 48, which is
>99% in the mouse, rat, and human,11 and presumably
high protein binding in the brain as well.
Further examination of the N-alkyl region focused on
the influence of the chiral center at the a-branched
position (Table 4). Examples 44–47 illustrate two
comparisons of (R) versus (S) isomers in the 4-methy-
phenylsulfonamide series. For the 2-butyl substituent,
the (R)-isomer 45 was >10-fold more potent than the
(S)-isomer 44. Likewise, with 2-pentyl analogues 46
and 47, the (R)-isomer 47 was more potent, although
in this case the difference in IC50 was >150-fold. In
examples 48–51, the chiral center is fixed in the (R)-con-
figuration and the optimized 4-chlorosulfonamide
substituent is held constant. Combination of the
In summary, potent c-secretase inhibitors resulting from
classic structure–activity relationship studies were
Table 4. Inhibitory activities of N-a-methylalkylsulfonamide enantiomers
OH
R1
Cl
N
O2S
R2
R1
R1
Ab40 IC50 (nM)
a
Exp. #
44
1300
100
3700
24
CH3
CH3
CH3
CH3
Cl
45
46
47
48
49
50
51
5.0
14
Cl
4.0
Cl
5.0
Cl
a Values are means of two experiments, with 12 drug concentrations in each exp.; intra-assay variance <10%.

4436
M. F. Parker et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4432–4436
Chaturvedula, P. V.; Deshpande, M. S.; Keavy, D. J.;
Lau, W. Y.; Parker, M. F.; Sloan, C. P.; Wallace, O. B.;
Wang, H. H. WO 0050391.
produced. These results demonstrate that a variety of
arylsulfonamides can be produced with low nanomolar
activities in a cell free assay. Compounds exemplified
by (R)-2-pentyl 48, were more than 100-fold more
potent than the original screening hit. This molecule also
reduced the concentration of Ab in the brain in trans-
genic Tg2576 mice. Subsequent communications will
describe our continued efforts to design compounds
possessing both improved Ab IC50’s and in vivo efficacy.
7. Smith, D. W.; Munoz, B.; Anderson, J.; Arruda, J.;
Barten, D.; Baskin, P.; Bergstrom, C.; Corsa, J.;
Felsenstein, K.; Guss, V.; Holtz, G.; Hu, Y.; Kounnas,
M.; Lau, W.; Loo, A.; Noonan, J.; Parker, M.; Polson,
C.; Roberts, S.; Roope, J.; Sloan, C.; Srinivasan, K.;
Tomlinson, R.; Tran, T.; Wagner, S.; Wallace, O.;
Wang, B.; Wang, R.; Wong, J.; Yang, F. Abstracts of
Papers, 228th ACS National Meeting, Philadelphia, PA,
United States, August 22–26, 2004, MEDI-337, AN
2004:658199.
References and notes
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Smith, D. W.; Pak, R. Isolation of a functionally active c-
secretase presenilin 1 complex and fluorescence assay for
c-secretase activity and inhibitors. PCT Int. Appl. WO01/
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