Tetrahydroquinoline sulfonamides as γ-secretase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2006.09.064

The development of a novel series of tetrahydroquinoline-derived γ-secretase inhibitors for the potential treatment of Alzheimer's disease is described.

Full text of DOI:10.1016/j.bmcl.2006.09.064

Bioorganic & Medicinal Chemistry Letters 17 (2007) 205–207
Tetrahydroquinoline sulfonamides as c-secretase inhibitors
Theodros Asberom,a,* Thomas A. Bara,a John W. Clader,a William J. Greenlee,a
Henry S. Guzik,a Hubert B. Josien,a Wei Li,a Eric M. Parker,b
Dmitri A. Pissarnitski,a Lixin Song,b Lili Zhangb and Zhiqiang Zhaoa
aDepartment of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
bDepartment of Central Nervous System Biology, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth,
NJ 07033, USA
Received 28 July 2006; revised 19 September 2006; accepted 21 September 2006
Available online 12 October 2006
Abstract—The development of a novel series of tetrahydroquinoline-derived c-secretase inhibitors for the potential treatment of
Alzheimer’s disease is described.
Ó 2006 Elsevier Ltd. All rights reserved.
Alzheimer’s disease (AD) is a progressive neurodegener-
ative disease characterized by memory loss and cognitive
decline. AD is the third largest cause of death and the
leading cause of dementia in the United States.1 A large
body of evidence strongly suggests that overproduction,
aggregation, and/or plaque deposition of the Ab pep-
tides, particularly Ab 42, are central to the pathogenesis
of AD.2 The Ab-peptides are produced by the sequential
proteolytic cleavage of the amyloid precursor protein
(APP) by b- and c-secretases, respectively. Because of
the essential role of c-secretase in the generation of Ab
peptides, c-secretase inhibition may be useful in the
treatment of AD. Selective regulation of APP cleavage
remains a critical issue because c-secretase is also known
to mediate a range of alternative transmembrane pep-
tides most notably the Notch receptor, a large single-
amide 2, a recently reported c-secretase inhibitor
pass membrane protein that is implicated in develop-
(IC50 = 25 nM).5 We further surmised that the ring
ment and differentiation.3 To date, several c-secretase
system in 1 could be simplified by elimination of the
inhibitors have been identified that lower Ab production
two asymmetric centers at the ring junction, and subse-
in intact cells and cell-free systems.4
quent installation of an appropriate carbamate side
chain at the 2-position could provide a novel tetrahydro-
quinoline c-secretase inhibitor as represented by 3. This
communication describes the synthesis of tetrahydro-
quinoline analogues which illustrate how substituents
on the heterocyclic and aromatic rings of the tetrahydro-
quinoline core relate to in vitro c-secretase activity.6
Screening of an in-house database provided several hits
with modest c-secretase inhibitory activity, one of which
was the bicyclic sulfonamide 1 (IC50 = 2.5 lM).
We presumed that the perhydroquinoline ring system in
1 could represent a ring constrained version of sulfon-
Synthesis of the tetrahydroquinoline analogues7 started
with reduction of quinaldic acid 4 followed by esterifica-
tion to give ester 5 (Scheme 1). The ester was reduced
with LAH to give amino-alcohol 6. The sulfonamide 7
Keywords: Sulfonamides; c-secretase inhibitors; Alzheimer’s disease.
Corresponding author. Tel.: +1 908 740 3467; fax: +1 908 740
7152; e-mail: theodros.asberom@spcop.com
*
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.09.064

206
T. Asberom et al. / Bioorg. Med. Chem. Lett. 17 (2007) 205–207
Scheme 1. Reagents and conditions: (i) a—H2, PtO2, MeOH; b—SOCl2; (ii) LAH, THF; (iii) a—TMSCl, Et3N, DCM, 0°C; b—ArSO2Cl, Et3N,
THF, reflux; (iv) K2CO3, MeOH, 0°C; (v) p-NO2–PhCOCl, CH3CN, pyr; (vi) R1R2NH, MeOH.
Table 1. Structure–activity relationships of carbamates
was prepared in a two-step, one-pot process by first pro-
tecting the alcohol as the silylether followed by sulfony-
lation. Deprotection provided the alcohol 8. After
activation as a p-nitrophenyl carbonate, the hydroxy-
methyl side chain was converted to carbamate 9, in
modular fashion, with a set of amines.
The structure–activity relationships of carbamate sub-
stituents are summarized in Table 1. Simple aliphatic
carbamates show modest c-secretase activity. However,
inhibition of c-secretase is significantly enhanced by
the incorporation of a nitrogen heteroatom in the side
chain (13 and 15). Furthermore, disubstituted carba-
mates with side chain bearing terminal amines showed
up to twofold improvement in potency compared with
the corresponding mono-substituted carbamates (13 vs
14, 15 vs 16, and 17 vs 18). Carbamates bearing amine
substituents bulkier than ethyl (R2 = benzyl, isopropyl)
suffered in potency. The disubstituted 4-picolinyl carba-
mate (18) gave the best activity in this study. Introduc-
tion of a second amine on the pyridine ring resulted in
a substantial loss in potency (19). Having identified po-
tent inhibitors, attention was directed toward the syn-
thesis of analogues with diverse substitution at the
terminus of the side chain.
Compound
R1
R2
H
IC50 (nM)8
1096
10
*
*
11
12
H
H
4488
2959
OH
NO2
*
*
13
14
15
H
Et
H
394
172
504
N
*
*
N
N
*
N
16
Et
253
N
N
N
17
18
H
1644
88
*
*
*
As shown in Table 2, terahydroquinoline analogues de-
rived from piperazine (20–22) and simple 4-amino piper-
idine (23 and 24) provide comparable potency to the
open chain carbamate analogues. A number of 4-amino
piperidine analogues bearing cyclic distal amines were
investigated. Piperidino-pyrolidine (25) and piperidino-
homopiperidine (29) were modestly equipotent whilst
piperidino-piperidine (26) proved to be most potent.
Compound (26) was selected for further evaluation
and was prepared in its enantiomerically pure form from
the chromatographically resolved alcohol (8).9 The rela-
tive potencies of the two enantiomers (27 and 28) indi-
cate enantiospecificity with respect to c-secretase
inhibition.
Et
19
Et
580
NH2
All compounds are racemic.
The effect of introducing fluorine substituents on the
phenyl ring of the tetrahydroquinoline was investigated
as outlined in Table 3. The compounds were prepared as
piperidino-piperidine carbamates.10 Introduction of two
fluorine atoms at the 5,7- and 5,8-positions of the phenyl
ring resulted in some loss of inhibitory activity (30 and

T. Asberom et al. / Bioorg. Med. Chem. Lett. 17 (2007) 205–207
Table 2. Structure–activity relationships of cyclic carbamates
207
31) and fluorine substitution at the 6-position (32)
proved to be highly detrimental. Incorporation of a fluo-
rine substituent at the 7-position, however, gave rise to
the most potent compound (33). Selected tetrahydro-
quinoline sulfonamides displayed poor pharmacokinetic
properties and further work was differed to the related
2,6-disubstituted N-arylsulfonyl piperidine class of com-
pounds which showed promising pharmacokinetic
properties.11
Compound
NR1R2
IC50 (nM)8
440
20
N
N
*
*
In conclusion, a novel series of tetrahydroquinoline sul-
fonamides that inhibit c-secretase has been discovered.
It was found that the potency of the screening hit 1
could be enhanced first by structural simplification to
a tetrahydroquinoline core and subsequently by the
introduction of appropriate substituents both on the
heterocyclic and phenyl rings of the tetrahydroquinoline
leading to compound 33.
N
N
21
22
23
24
299
540
680
629
OH
*
*
N
N
N
NH2
N(CH3)2
N
N
25
26
290
73
N
N
*
*
References and notes
1. Ewbank, D. C. Am. J. Public Health 1999, 89, 90.
2. Hardy, J.; Selkoe, D. J. Science 2002, 297, 353.
3. De Strooper, B.; Annaert, W.; Cupers, P.; Saftig, P.;
Craessaerts, K.; Mumms, J. S. Nature 1999, 398,
518.
N
N
N
*
27
39
4. (a) Churcher, I.; Beher, D. Curr. Pharm. Des. 2005, 11,
3363; (b) Josien, H. Curr. Opin. Drug Discovery Dev. 2002,
5, 513.
5. Smith, D. W.; Munoz, B. WO 50391, 2000 CAN
133:207678.
6. Preliminary SAR studies carried out on the perhydro-
quinoline lead series 1 established sulfonamide as opti-
mum substituent on the ring nitrogen (unpublished result).
7. Asberom, T.; Guzik, H.; Josien, H.; Pissarnitski, D. WO
14075, 2003 CAN 138:187649.
enantiomer a
N
N
*
28
29
>1000
255
enantiomer b
N
*
N
All compounds are racemic unless otherwise stated.
8. Zhang, L.; Song, L.; Terracina, G.; Liu, Y.; Pramanik, B.;
Parker, E. Biochemistry 2001, 40, 5049, all IC50 data
shown are average of minimum of three independent
results..
9. The two enantiomers of 8 (X = H) were separated by
preparative HPLC. The following conditions were used
for AS Chiralpack column: hexane/isopropanol, 90/10,
45 mL/min, 254 nM, 117.41 min (isomer A), 256.51 min
(isomer B). Each enantiomer was independently converted
to the enantiomerically pure carbamate.
Table 3. Structure–activity relationship of fluorine substitution on
aromatic ring of tetrahydroquinoline
10. The compounds listed in Table 3 were prepared in
analogous fashion to the compounds listed in Table 1.
The requisite fluorinated 2-methyl Quinoline starting
materials were prepared using Doebner–Miller quinoline
synthesis as modified by Matsugi, M.; Tabusa, F.;
Minimikawa, J. Tetrahedron Lett. 2000, 8523.
11. Pissarnitski, V. A.; Asberom, T.; Bara, A. T.; Buevich, V.
A.; Clader, W. J.; Greenlee, J. W.; Guzik, S. H.; Josien, B.
H.; Li, W.; McEwan, M.; McKittrick, A. B.; Nechuta, L.
T.; Nomeir, A. A.; Sinning, L.; Smith, M. E.; Parker, M.
E.; Vaccaro, A. H.; Voight, H. J.; Zhang, L.; Zhao, Z.;
Bioorg. Med. Chem. Lett. in press.
Compound
X
IC50 (nM)8
26
30
31
32
33
H
73
219
5,7-F2
5,8-F2
6-F
217
>1000
56
7-F
All compounds are racemic.