Tricyclic sulfones as orally active γ-secretase inhibitors: Synthesis and structure-activity relationship studies

Article abstract of DOI:10.1016/j.bmcl.2010.04.104

Tricyclic sulfones were designed as γ-secretase inhibitors and found to have excellent potency. Extensive SAR shows that a large number of sulfonamides at position 7 of the tricycle are very well tolerated. Compounds such as 15a and 15c showed remarkable in vivo potency.

Full text of DOI:10.1016/j.bmcl.2010.04.104

Bioorganic & Medicinal Chemistry Letters 20 (2010) 3632–3635
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Tricyclic sulfones as orally active c-secretase inhibitors: Synthesis
and structure–activity relationship studies
*
T. K. Sasikumar , Li Qiang, Duane A. Burnett, David Cole, Ruo Xu, Hongmei Li, William J. Greenlee,
John Clader, Lili Zhang, Lynn Hyde
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Tricyclic sulfones were designed as c-secretase inhibitors and found to have excellent potency. Extensive
Received 31 March 2010
Revised 21 April 2010
Accepted 23 April 2010
Available online 5 May 2010
SAR shows that a large number of sulfonamides at position 7 of the tricycle are very well tolerated. Com-
pounds such as 15a and 15c showed remarkable in vivo potency.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
c
-Secretase
Alzheimer’s disease
Sulfone
Alzheimer’s disease (AD) is a progressive neurodegenerative
disease. The Ab peptide (40–42 amino acids) is the major constitu-
tricyclic core structure (8) as well as some SAR on the sulfone aryl
ring.
ent of plaques found in AD patients brain. Inhibition of
c
-secretase,
The preparation of tricyclic compounds described in this letter
is illustrated in Scheme 1. The enolate derived from valerolactone
was added to vinyl sulfone (9) to obtain compound 10 in 86% yield.
The lactone ring was opened with Mg(OMe)2 in methanol followed
by mesylation and cyclization under KOtBu conditions to give the
tricyclic compound 12. Only one diastereoisomer was observed
in this reaction.12b The ester group was reduced to the alcohol 13
in excellent yield. At this stage, the enantiomers were separated
on a Chiralcel OD column. The (À) enantiomer (13a) was used
for further SAR studies since the (+) enantiomer showed decrease
one of the enzymes responsible for the cleavage of the amyloid
precursor protein (APP) to produce the pathogenic Ab-peptides,
is an attractive approach to the treatment of AD. Because inhibition
of
c-secretase blocks the production of Ab, the identification of
compounds that block the activity of this enzyme has become a
major focus of AD research.1–5
A large number of simple sulfonamide based c-secretase inhibi-
tors (1, 2)6–9 have appeared in recent literature. The carbon analog
of a sulfonamide, a sulfone (3), was designed and reported to have
excellent
c
-secretase activity.10 The conformationally restricted
compound 4 was also discovered (Fig. 1).11 Based on the literature,
together with our in house data, we designed and synthesized first
generation bicyclic sulfones (5), that lead to the second generation
tricyclic sulfone (6) as shown in Figure 2.12a A series of SAR studies
on the cyclohexyl ring of compound 6 lead us to a number of sulfon-
amidecompounds(atposition8)asillustratedbystructure7withan
improved affinity and pharmacokinetic properties.12a Further SAR
development in this tricyclic series shown that position 7 is also very
F
R1
N
OH
O
F
N
S
N
S
R2
O
O
O
O
O
Cl
Cl
1
2
well tolerated and we have generated a number of c-secretase inhib-
itors with excellent in vitro potency and in vivo efficacy. This paper
F
F
NHSO2R
describes the synthesis and SAR development at position 7 of the
F
F
OH
O
O
O
O
S
S
Cl
Cl
3
4
* Corresponding author. Tel.: +1 908 740 4373; fax: +1 908 740 7164.
E-mail addresses: sasikumartk@yahoo.com, thavalakulamgar.sasikumar@-
merck.com (T.K. Sasikumar).
Figure 1. Early c-secretase inhibitors.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.04.104

T. K. Sasikumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3632–3635
3633
F
F
F
F
F
4
O
O
O
O
S
O
O
H
H
H
7
S
N
R2
R
S
7
1
O
F
R3
F
F
N
H
O S O
8
O
O
O S O
O S O
O
R1
Cl
Cl
IC50 = 13 nM
Cl
7
IC50 = 27 nM (R = CF3)
5
6
IC50 = 42 nM
8
Figure 2. Design of tricyclic
c
-secretase inhibitors.
F
F
F
F
F
F
O
O
O
S
O
S
O
O
O
O
O
H
H
a
b, c
d
e
OH
O
O
F
F
F
F
O
O
O
O
O
S
O
O S O
O S O
OMs
CF3
CF3
CF3
CF3
CF3 ( )
13
f-i
9
10
11
12
F
F
F
F
F
F
F
F
O
O
O
O
O
O
O
O
H
H
H
j
a-j
S
S
N
R
NH2
N
R
H
H
O
S
O
O S O
O S O
O S O
Cl
CF3 (-)
15 a-g
CF3 (-)
14
Cl
16
17 a-r
Scheme 1. Reagents and conditions: (a) LHMDS, valerolactone, THF, À78 °C, 86%; (b) Mg(OMe)2, MeOH, 71%; (c) MsCl, TEA, DCM; (d) KOtBu, THF, 74% (two steps); (e) LiBH4,
THF, 91%; (f) Chiral separation on Chiralcel OD Column, 45%; (g) MsCl/TEA, DCM; (h) NaN3, DMF; (i) Ph3P, H2O, THF, 94% (three steps); (j) RSO2Cl, TEA, DCM (for R = Me, 97%).
F
F
F
F
O
O
O
O
O
O
O
O
H
H
H
H
S
R2
a
b
c
OH
H
NH
R1
N
F
F
F
F
R1
O S O
O S O
O S O
O S
CF3
CF3
CF3
CF3
13a
18
19
20 a-f
d
F
F
F
F
O
O
O
O
O
O
O
H
H
H
e
S
S
R2
OMs
N
X
N
R1
F
F
n
O S O
O S O
O S O
CF3
Cl
21 a-e
CF3
13b
20 g-j
Scheme 2. Reagents and conditions: (a) Dess–Martin Periodinane, DCM, 90%; (b) R1NH2, Na(OAc)3BH, DCM, 80–85%; (c) R2SO2Cl, TEA, DCM, 80–90%; (d) MsCl, TEA, DCM,
98%; (e) five or six-membered sultam, NaH, THF; cyclic sulfamide, NaH, THF, 50–60%.

3634
T. K. Sasikumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3632–3635
-secretase assay.13 The (À) alcohol obtained was
Table 1
in potency in the
c
c
-Secretase membrane and cell IC50’s
mesylated and treated with NaN3 followed by reduction afforded
the tricyclic amine 14 in 94% overall yield. Sulfonamide com-
pounds 15a–g were prepared by standard sulfonylation methods.
Similarly compounds 17a–r were prepared starting from the chlo-
rophenyl vinyl sulfone 16 as shown in Scheme 1.
Enantiomerically pure tricyclic alcohol 13a was oxidized to the
aldehyde 18 followed by reductive amination using various amines
to afford 19. Amines 19 were then sulfonylated under standard reac-
F
O
O
O
H
S
N
R2
H
F
O S O
15 a-g
17 a-r
R1
Table 3
Profile of 15a and 15c
Compd
R1
R2
Membranea
IC50 (nM)
Cell Ab40
IC50 (nM)
Cell Ab42
IC50 (nM)
F
15a
15b
15c
15d
15e
15f
15g
17a
17b
17c
17d
17e
17f
17g
17h
17i
17j
17k
17l
CF3
CF3
CF3
CF3
CF3
CF3
CF3
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
CH3
CH2CH3
CF3
CH2CF3
cPr
NH2
NMe2
CH3
CF3
CH2CH3
CH2CF3
CH2CH2CH3
CH2CH2CH2CH3
CH2CH2COOEt
iPr
cPr
Cyclohexyl
NH2
NMe2
NEt2
Pyrrolidinyl
Piperidinyl
Morpholinyl
Ph
2-Thienyl
2,6-diF-Ph
13
20
41.7
25
19.7
18.7
6.8
2.5
12
1.6
7.8
5.5
13
12
5.5
40.6
22.7
17.5
6
12.7
2
18
4
16
12
29
4
12
4
60
1
2
3.6
1.6
1.6
8
6.3
4
5.4
2
9
2
4
6
13
3
O
O
O
H
S
N
R
H
F
O S O
15 a; R = CH3
CF3 15 c;
R = CF3
Parameters
R = CH3 (15a)
R = CF3 (15c)
Membrane IC50 (nM)
Cell IC50 (nM) Ab40, Ab42
Caco-2 permeability
Efflux substrate
13
41.7
2
12, 3.6
421 nm/s
No
>30
2006
40.6, 18.7
230 nm/s
No
5.2
3.1
55
2
2.7
9
3.3
6
3.4
61
16.7
13
5
4
20
1
1
CYP 3A4 (
l
M)a
>30
Rat PK (10 mg/kg PO)
702b
AUC (ng h/mL)15
17m
17n
17o
17p
17q
17r
17s
6
5
3
3
Brain concn @ 6 h (ng/g)
Brain/plasma ratio
h-Plasma protein binding
80
0.73
98.1
91
1.01
99.9
Cl
Cl
Cl
Cl
Cl
Cl
19
6
128
45
32
11
3
46
18
17
Non TG % inhibition at 3 h (10 mg/kg po) 96 (pl), 69 (br) 101 (pl), 71 (br)
a
Values determined after 30 min pre-incubation with compound.
A slight increase in AUC was observed when sodium salt of 15c was prepared.
b
a
Free base AUC was 400 ng h/mL.
Mean values (n = 2) SEM.
Table 2
-Secretase membrane and cell IC50’s
c
F
F
F
O
O
O
H
O
O
O O
O
O
H
H
S
S
S
R
N
R2
N
N
N
F
F
F
R1
n
O S O
O S O
O S O
20 g
20 h
20 i
20 j
, n = 1
, n = 2
, R = H
CF3
CF3
R
20 a-f (R = CF3)
21 a-e (R = Cl)
, R = CH3
Compd
R1
R2
Membranea
IC50 (nM)
Cell Ab40
IC50 (nM)
Cell Ab42
IC50 (nM)
20a
20b
20c
20d
20e
20f
20g
20h
20i
CH2CH3
CH2CH3
CH2CH3
cPr
cPr
cPr
—
—
—
—
CH3
CF3
cPr
CH3
CH2CH3
CF3
—
—
—
—
CH3
CH2CH3
cPr
CH3
CF3
34
97
83
5.8
28
35.3
90
122
37.7
68
5.5
16
20.5
3.3
15
18.5
42
46.7
9
29.5
15.3
72
na
na
23
12
7.4
21
21
6
14.2
14.2
25
na
na
13
5
20j
21a
21b
21c
21d
21e
CH2CH3
CH2CH3
CH2CH3
cPr
15
25
6
21
7
9
4
9
cPr
a
Mean values (n = 2) SEM. na = not available.

T. K. Sasikumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3632–3635
3635
tion conditions to give compounds 20a–f as shown in Scheme 2.
References and notes
Alcohol 13a was mesylated and displaced with sultam or cyclic sul-
fonamide to produce compounds 20g–j as shown in Scheme 2. Sim-
ilar chemistry was utilized for the preparation of compounds 21a–e.
The SAR derived from the tricyclic scaffold is described in Table
1. Alkyl sulfonamides such as methyl (15a), ethyl (15b), trifluoro-
methyl (15c), trifluoroethyl (15d), and cyclopropyl (15e) deriva-
tives showed excellent potency in the membrane as well as
cellular assays. Simple sulfamides such as 15f and 15g were also
very well tolerated. The sulfonamide SAR in the chlorophenyl sul-
fone series showed excellent potency; usually several fold
enhancement relative to the trifluoromethylphenyl sulfone series.
However, that difference in potency did not really translate into
in vivo efficacy. Both series generally produce very similar
in vivo numbers.14 In the chlorophenyl sulfone series, a wide range
of alkyl sulfonamides are tolerated as shown in Table 1. Long alkyl
chains (17a–h) as well as small cyclic alkyls (17i) are very well tol-
erated. Cyclohexyl (17j) and phenyl (17q) sulfonamides showed a
decrease in potency, however, 2,6-difluorophenyl (17r) and 2-thi-
enyl (17s) sulfonamides showed very good in vitro affinity. The
sulfamide analogs 17k–p are also very well tolerated.
1. Hardy, J.; Allsop, D. Trends Pharmacol. Sci. 1991, 12, 383.
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Deshpande, M. S.; Keavy, D. J.; Lau, W. Y.; Parker, M. F.; Sloan, C. P.; Wallace, O.
B.; Wang, H. H. WO 200050391.
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Deshpande, M. S.; Felsenstein, K. M.; Guss, V. L.; Hansel, S. B.; Johnson, G.;
Keavy, D. J.; Lau, W. Y.; Mock, J.; Prasad, C. V. C.; Polson, C. T.; Sloan, C. P.; Smith,
D. W.; Wallace, O. B.; Wang, H. H.; Williams, A.; Zheng, M. Bioorg. Med. Chem.
Lett. 2007, 17, 4432.
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Li, W.; Parker, E. M.; Pissarnitski, D. A.; Song, L.; Zhang, L.; Zhao, Z. Bioorg. Med.
Chem. Lett. 2007, 17, 205.
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15, 2685.
11. Churcher, I.; Beher, D.; Best, J. D.; Castro, J. L.; Clarke, E. E.; Gentry, A.; Harrison,
T.; Hitzel, L.; Kay, E.; Kerrad, S.; Lewis, H. D.; Morentin-Gutierrez, P.;
Mortishire-Smith, R.; Oakley, P. J.; Reilly, M.; Shaw, D. E.; Shearman, M. S.;
Teall, M. R.; Williams, S.; Wrigley, J. D. J. Bioorg. Med. Chem. Lett. 2006, 16, 280.
12. (a) Xu, R.; Cole, D.; Asberom, D.; Bara, T.; Bennett, C.; Burnett, D.; Clader, J.;
Domalski, M.; Greenlee, W.; Hyde, L.; Josien, H.; Li, H.; McBriar, M.; McKittrick,
B.; Pissarnitski, D.; Qiang, L.; Rajagopalan, M.; Sasikumar, T.; Su, J.; Tang, H.;
Wu, W.-L.; Zhang, L.; Zhao, Z. Bioorg. Med. Chem. Lett. 2010, 20, 2591; (b) NMR
data for compound 12: 1H NMR (CDCl3, 400 MHz) d 7.80 (m, 4H), 7.08 (m, 1H),
6.42 (m, 1H), 5.16 (d, 1H), 4.22 (d, 1H), 3.71 (s, 3H), 3.02 (d, 1H), 2.60 (d, 1H),
2.45 (m, 1H), 1.97 (m, 2H), 1.75 (m, 1H), 1.58 (m, 1H), 1.07 (m, 1H).
Next, we turned our attention to N-alkyl substituted sulfona-
mides as shown in Table 2. We have introduced ethyl and cyclo-
propyl substitutions on the nitrogen atom. Simple methane
sulfonamide (20a) in this series showed 34 nM activity whereas
trifluoromethyl (20b) and cyclopropyl (20c) sulfonamides showed
diminished
c-secretase affinity. Sultam derivatives 20g and 20h
F
showed less potency than the corresponding acyclic version and
the cyclic sulfamide derivatives 20i and 20j were also showed
F
O
H
2
3
O
diminished
c-secretase activity. As expected, the chlorophenyl sul-
H
O
4
H
fone derivatives 21a–e exhibited better
c-secretase activity than
O
O
5
6
F
their trifluoromethyl phenylsulfone analogs.
As described in Tables 1 and 2, SAR studies on the sulfonamide
series led to the identification of a large number of potent c-secre-
F
O
O S O
O
S
O
H
tase inhibitors. Mouse efficacy and pharmacokinetic studies were
carried out on numerous compounds and used as a key assay to dis-
criminate better analogs. Data for two of the best compounds 15a
and 15c are shown in Table 3. These compounds are orally bioavail-
ableandshowedexcellentinvivoefficacyin anon-transgenicmouse
model as shown in Table 3. Compound 15a showed 96% inhibition of
Ab40 in the plasma and 69% inhibition in the brain at 10 mg/kg po.
Compound 15c also showed excellent inhibition both in plasma
(101%) and brain (71%). It has been found that compounds 15a and
CF3
J = 12 Hz (H3 and H5; trans)
Compound 12
F
F
F
13. Efficacy of
cells expressing human APP with both Swedish and London mutations. The
cells were grown in 96-well plate with 100 L media per well, and were
changed to fresh media and incubated with -secretase inhibitor for 4 h. Ten
c-secretase inhibitors in intact cells was measured using HEK293
l
c
microliters of conditioned media was used to measure Ab40 using ECL
technology as described in the following reference. Zhang, L.; Song, L.;
Terracina, G.; Liu, Y.; Pramanik, B.; Parker, E. Biochemistry 2001, 40, 5049.
14. For example, Compound 17b showed 86% inhibition of Ab40 in plasma and 48%
in brain at 10 mg/kg po and compound 15c showed 101% inhibition of Ab40 in
plasma and 71% in brain at 10 mg/kg po.
15. Following the oral dosing at 10 mpk in 20% HPBCD, AUC in rats was measured
over a period of 6 h, using cassette-accelerated rapid rat screen (CARRS):
Korfmacher, W. A.; Cox, K. A.; Ng, K. J.; Veals, J.; Hsieh, Y.; Wainhaus, S.; Broske, L.;
Prelusky, D.; Nomeir, A.; White, R. E. Rapid Commun. Mass Spectrom. 2001, 15,
335.
15c are inactive @ 30 lM in the P450 assay as well as in the hERG
channel. The triflimide compound 15c is highly protein bound. Both
compounds are well absorbed and are not PGP efflux substrates.
In summary, we have identified a large number of highly po-
tent, small molecule inhibitors that display excellent in vivo effi-
cacy in rodents. Compounds 15a and 15c have excellent profile
and are potent in vivo. Further biological characterization of these
compounds will be presented in due course.