Structure activity relationship studies of tricyclic bispyran sulfone γ-secretase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.11.047

An investigation is detailed of the structure activity relationships (SAR) of two sulfone side chains of compound (-)-1a (SCH 900229), a potent, PS1-selective γ-secretase inhibitor and clinical candidate for the treatment of Alzheimer's disease. Specifically, 4-CF₃ and 4-Br substituted arylsulfone analogs, (-)-1b and (-)-1c, are equipotent to compound (-)-1a. On the right hand side chain, linker size and terminal substituents of the pendant sulfone group are also investigated.

Full text of DOI:10.1016/j.bmcl.2012.11.047

Bioorganic & Medicinal Chemistry Letters 23 (2013) 844–849
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure activity relationship studies of tricyclic bispyran sulfone
c-secretase inhibitors
⇑
Wen-Lian Wu , Theodros Asberom, Thomas Bara, Chad Bennett, Duane A. Burnett, John Clader,
Martin Domalski, William J. Greenlee, Hubert Josien, Mark McBriar, Murali Rajagopalan, Monica Vicarel,
Ruo Xu, Lynn A. Hyde, Robert A. Del Vecchio, Mary E. Cohen-Williams, Lixin Song, Julie Lee,
Giuseppe Terracina, Qi Zhang, Amin Nomeir, Eric M. Parker, Lili Zhang
Merck Research Laboratories, 2015 Galloping Hill Rd, 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:
Available online 24 November 2012
An investigation is detailed of the structure activity relationships (SAR) of two sulfone side chains of com-
pound (ꢀ)-1a (SCH 900229), a potent, PS1-selective
c-secretase inhibitor and clinical candidate for the
treatment of Alzheimer’s disease. Specifically, 4-CF3 and 4-Br substituted arylsulfone analogs, (ꢀ)-1b
and (ꢀ)-1c, are equipotent to compound (ꢀ)-1a. On the right hand side chain, linker size and terminal
substituents of the pendant sulfone group are also investigated.
Keywords:
Alzheimer’s disease
c
-Secretase inhibitor
Ó 2012 Elsevier Ltd. All rights reserved.
Structure activity relationship
Sulfone
Alzheimer’s disease (AD) is the sixth-leading cause of death in
the United States, affecting 5.4 million people, according to a re-
cent estimate by the Alzheimer’s Association.1 AD is the most com-
mon form of dementia, resulting from damage and death of
neurons. Current treatments, chiefly the cholinesterase inhibitors,
only help to ease symptoms.2 In search of better treatments, great
efforts have been devoted to the understanding of the biochemical
mechanism and pathology of the disease. A leading scientific ratio-
nale regarding the cause of AD is the amyloid hypothesis, which
stipulates that accumulation of b-amyloid peptides (Ab) leads to
the death of neurons and eventually results in plaque formation.3
A recent genetic study strongly supports this notion.4 Thus, block-
ade of Ab production might mitigate or even reverse the disease
course and thus provide a disease-modifying therapy. Amyloid is
generated from a large transmembrane glycoprotein called amy-
loid precursor protein (APP). APP is processed first by BACE1 to a
decades, resulting in many structurally diverse small molecule
c
-secretase inhibitors (GSIs).7
We previously described the discovery of a novel
c-secretase
inhibitor (ꢀ)-1a.8 Herein, a detailed SAR exploration of the two sul-
fone side chains of the molecule will be discussed, as illustrated in
Figure 1.
The synthesis of the bispyran tricyclic scaffold ( )-8a–8f com-
menced with readily available compound 2, as depicted in Scheme
1. Michael addition of substituted thiophenols to 2 gave racemic
adducts 3a–3f in nearly quantitative yield. After reduction of the
two ester groups with lithium aluminum hydride, the resultant
diols were treated with potassium tert-butoxide to effect ring
closure to provide alcohols 4a–4f. Oxidation of the primary alco-
hols gave aldehyde intermediates9 that were converted to their
C99 fragment that is further cleaved by
c
-secretase to generate a
F
variety of short peptides, Ab37-42.5 However,
c-secretase also
F
O
plays important roles in other biological processes, notably the
O
O
O
H
O
n=1-3
H
O
Notch pathway, which is involved in cell growth and differentia-
S
R
tion.6 Thus, discovery and development of
c-secretase inhibitors
S
O O
F
S
F
as a treatment for AD have been hampered by challenges to
achieve substrate selectivity, especially against the Notch pathway.
Toward this end, great efforts have been made during the past two
S
O
O
O
O
X
Cl
(-)-1a
SCH 900229
⇑
Corresponding author. Tel.: +1 732 594 2987; fax: +1 732 594 3007.
E-mail address: wen-lian.wu@merck.com (W.-L. Wu).
Figure 1. c-Secretase inhibitor SCH 900229 and SAR development.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.11.047

W.-L. Wu et al. / Bioorg. Med. Chem. Lett. 23 (2013) 844–849
845
F
F
F
F
O
S
O
S
F
S
COOMe
F
F
O
OH
F
COOMe
a
b, c
d, e
COOMe
COOMe
O
F
F
X
X
X
2
( )-3a-f
( )-4a-f
( )-5a-f
F
F
F
F
F
O
O
O
S
O
S
H
O
H
O
H
O
f, g
i, j
+
F
O
or
h, f
S
1
O
O
OH
O
O
OH
X
X
X
3
5
( )-6a-f
( )-7a-f
( )-8a X = 4-Cl
( )-8b X = 4-CF3
( )-8c X = 4-Br
( )-8d X = 4-F
( )-8e X = 3,4-F,F
( )-8f X = 3,5-F,F
Scheme 1. Reagents and conditions: (a) ArSH, K2CO3, THF, ꢁ100%; (b) LiAlH4, THF, ꢁ50%; (c) t-BuOK, THF, 85–95%; (d) Dess–Martin periodinane, CH2Cl2, 90%; (e)
(TMSOCH2)2, TMSOTf, ꢁ90%; (f) allyltrimethylsilane, BF3–OEt2, CH2Cl2, 30–40% for desired diastereoisomers; (g) potassium peroxomonosulfate, MeCOMe–H2O, 60–70%; (h)
mCPBA, CH2Cl2, ꢁ90%; (i) MsCl, Et3N, CH2Cl2; (j) t-BuOK, THF, >80% for two steps.
corresponding acetals 5a–5f. Acetal 5a was first treated with allyl-
trimethylsilane under Lewis acid catalysis10 followed by sulfide
oxidation with potassium peroxomonosulfate to afford two diaste-
reoisomers 6a and 7a in a ratio of approximately 1:2. Compounds
6d and 7d were obtained by a similar route from acetal 5d.
Alternatively, acetals 5–b, c, e, f were first oxidized with mCPBA
to give sulfones followed by acetal ring opening to provide corre-
sponding diastereomers 6–b, c, e, f and 7–b, c, e, f. The overall
yields of the desired isomers 7a–7f were comparable by these
two approaches. Alcohols 7a–7f were activated with mesyl
F
F
F
O
O
O
H
H
O
H
O
OH
OH
a, b
d
F
F
F
O
S
S
S
O
O
O
O
O
O
X
X
X
( )-8a X = 4-Cl
( )-8b X = 4-CF3
( )-8c X = 4-Br
( )-9a-h
(-)-9a X = 4-Cl
(-)-9b X = 4-CF3
(-)-9c X = 4-Br
( )-8d X = 4-F
(-)-9e X = 3,4-F,F
(-)-9f X = 3,5-F,F
(-)-9g X = 4-OMe
(-)-9h X = 4-OCH2CF3
(-)-9i X = 4-CN
( )-8e X = 3,4-F,F
( )-8f X = 3,5-F,F
( )-8g X = 4-OMe
( )-8h X = 4-OCH2CF3
c
e
f
(-)-9j X = 3,4-CN,CN
F
F
O
O
O O
S
H
O
H
O
OTs
g
h
F
F
S
S
O
O
O
O
X
X
(-)-10a-j
(-)-1a-j
Scheme 2. Reagents and conditions: (a) O3, dichloromethane; (b) Ph3P, NaBH4, >90% in two steps; (c) MeOH or CF3CH2OH, NaH, DMF, 80 °C, ꢁ80%; (d) Chiral HPLC separation,
40–45%; (e) Zn(CN)2, Zn powder, Pd2(dba)3, dppf, DMF, 150 °C, 70%; (f) KCN, CH3CN, 23%; (g) TsCl, Et3N; (h) n-Bu4NI, MeSO2Na, THF, 70–80%.

846
W.-L. Wu et al. / Bioorg. Med. Chem. Lett. 23 (2013) 844–849
F
F
F
F
O
O
O
H
O
H
O
H
O
b, c
a
OH
F
F
S
S
S
O
O
O
O
O
O
Cl
Cl
Cl
( )-8a
( )-11
( )-12
F
F
F
O
O
H
O
H
OTs
S
O O
d
e
F
O
S
S
O
O
O
O
Cl
( )-13
Cl
( )-14
Scheme 3. Reagents and conditions: (a) RhCl3–3H2O, EtOH, reflux, ꢁ100%; (b) O3, CH2Cl2; (c) Ph3P, NaBH4, 92% for two steps; (d) TsCl, Et3N, CH2Cl2; (e) n-Bu4NI, MeSO2Na,
THF.
chloride, and the resultant intermediates were further treated with
base at room temperature to smoothly furnish the tricyclic allyl
compounds ( )-8a–8f.
tion reactions, with and without catalysis.12 The resolved alcohols
were converted to their tosylate derivatives (ꢀ)-10a–10j that were
then treated with n-tetrabutylammonium iodide and sodium
methanesulfinate in one-pot to give the final targets (ꢀ)-1a–1j as
major products, with small amounts of O-alkylation products
formed as well (structures not shown).13
The above reaction schemes enabled us to complete our SAR
investigations on the sulfone phenyl ring. Before we investigated
the SAR of the right-hand sulfone substitution, we first determined
the optimal linker size of that side chain. The one carbon-linked tri-
cyclic sulfone was prepared according to Scheme 3, starting from
the allyl compound ( )-8a. Double-bond migration catalyzed by
RhCl3–3H2O gave nearly quantitative yield of ( )-11.14 Cleavage of
the internal double bond by ozonolysis and reduction with Ph3P
and NaBH4 in one-pot gave the hydroxymethyl compound ( )-12.
After conversion of ( )-12 to its tosylate derivative ( )-13, treatment
with n-tetrabutylammonium iodide and sodium methanesulfinate
in one-pot furnished sulfone ( )-14.
With these versatile intermediates at hand, we next elaborated
the allyl side chains into methyl sulfone analogs (ꢀ)-1a–1j, as illus-
trated in Scheme 2. Initially, the 4-F substituent of compound ( )-
4d was displaced with methanol or trifluoroethanol under basic
conditions to give intermediates ( )-8g and ( )-8h, respectively.11
Ozonolysis and reductive workup of allyl compounds ( )-8a–8h
provided alcohols ( )-9a–9h. The racemic alcohols were resolved
by chiral HPLC (Chiralcel OJ or OD columns) to give the desired
enantiomerically pure materials (ꢀ)-9a–9h. The 4-CN substituted
alcohol (ꢀ)-9i and 3,4-dicyano substituted alcohol (ꢀ)-9j were pre-
pared from intermediate (ꢀ)-9a and (ꢀ)-9e respectively by cyana-
F
F
O
O
O
O
H
O
H
O
OH
S
a, b
Similarly, racemic ( )-1a was prepared from alcohol ( )-9a
using the same two-step procedure previously outlined in Scheme
2 for the chiral material (Scheme 4). On the other hand, the three
carbon-linked sulfone ( )-15 was obtained directly in modest yield
by treatment of the tosylate intermediate of ( )-9a with an anion
generated from dimethyl sulfone with LiHMDS.
F
F
S
S
O
O
O
O
Cl
Cl
Comparison of the three racemic sulfones that varied by side
chain length clearly indicated the two-carbon linker was optimal:
Ab40 membrane IC50, ( )-1a (18.6 nM) < ( )-15 (52 nM) < ( )-14
(151 nM). Thus, we focused on two-carbon linker side chains for
sulfone substituent SAR. As shown in Scheme 5, treatment of tos-
ylate (ꢀ)-10a with sodium trifluoromethylsulfinate salt and n-tet-
rabutylammonium iodide gave trifluoromethyl sulfone (ꢀ)-16a.
Alternatively, other sulfone analogs (ꢀ)-16b–16h with various
substituents on the right-hand side were prepared by displace-
ment of the tosyl group of (ꢀ)-10a with alkyl or heteroaryl thiols
followed by mCPBA oxidation of the resultant sulfide intermedi-
ates.8 Furthermore, the cyclopropyl sulfone (ꢀ)-16i was prepared
from the hydroxypropyl sulfone (ꢀ)-16g by activation of the hy-
droxyl group and base-promoted ring closure.15
( )-9a
( )-1a
a, c
F
F
O
H
O
S
O O
S
O
O
Cl
( )-15
Compounds (ꢀ)-1a–1j and (ꢀ)-16a–16l were subjected to,
Scheme 4. Reagents and conditions: (a) TsCl, Et3N, 95%; (b) n-Bu4NI, MeSO2Na,
THF, 80%; (c) MeSO2Me, LiHMDS, THF, 31%.
membrane-based and cell-based in vitro assays.16,17 As shown in

W.-L. Wu et al. / Bioorg. Med. Chem. Lett. 23 (2013) 844–849
847
F
F
F
F
As revealed in Table 2, for the 4-Cl substituted phenyl sulfone
series 16, many groups on the right-hand side chain, whether lipo-
philic or hydrophilic, were well tolerated in terms of their in vitro
potency. This tolerance suggests that these substituents might not
interact with the enzyme and do not contribute to the binding en-
ergy. Despite their similar in vitro potency, their in vivo efficacy
varied widely when dosed orally in mice. While non-polar groups,
such as (ꢀ)-16b, (ꢀ)-16c, (ꢀ)-16e, and (ꢀ)-16i lowered Ab in both
plasma and cortex significantly, polar substituted analogs, such as
(ꢀ)-16f and (ꢀ)-16h, were less efficacious. With an extra H-bond
donor, those analogs suffered from poor membrane permeability
and low brain penetration (B/P ratios are between 0.1 and 0.2 at
6 h in rats). While imidazole substituted compound (ꢀ)-16j dis-
played good efficacy, triazole analog (ꢀ)-16k with lower pKa and
higher polar surface area (PSA) did not reduce Ab at the time point
of 3 h.
O
O
O
S
O
H
O
H
O
OTs
CF3
a
S
S
O
O
O
O
Cl
Cl
(-)-10a
(-)-16a
b, c
(-)-16b R = Et
(-)-16c R = n-Pr
F
F
(-)-16d R = i-Pr
(-)-16e R = CH2CF3
(-)-16f R = (CH2)2OH
(-)-16g R = (CH2)3OH
(-)-16h R = CH2COOH
O
O
S
O
H
O
R
d,e
Among those potent
c-secretase inhibitors mentioned above,
(-)-16i R = cyclo-Pr
S
O
O
N
analog (ꢀ)-1b was most interesting and was thus selected for fur-
ther studies. As expected based on its screening data, (ꢀ)-1b dem-
onstrated excellent in vivo potency in a dose-response study (PO)
in B6C3F1 mice, with ED50 values of 7.7 mg/kg in plasma and
8.0 mg/kg in cortex. In rats, the ED50 values were measured to be
1.9, 2.8 and 7.4 mg/kg PO for plasma, cortex and CSF, respectively.
Compound (ꢀ)-1b displayed an IC50 of 31 nM in an in vitro cell-
based Notch cleavage assay.17 However, similar to (ꢀ)-1a, it is a
(-)-16j R =
HN
N
(-)-16k R =
N
HN
Cl
N
N
(-)-16l R =
HN
Scheme 5. Reagents and conditions: (a) n-Bu4NI, CF3SO2Na, THF, 60%; (b) RSH,
KOH, EtOH, 70 °C; (c) mCPBA, CH2Cl2, 60–80% for two steps; (d) MsCl, Et3N, CH2Cl2;
(e) t-BuOK, THF, ꢁ75% for two steps.
PS1 selective inhibitor of c-secretase with a high PS2/PS1 ratio of
19.8,19 Compound (ꢀ)-1b showed a favorable ancillary profile, for
Table 1, among the various substituted phenyl sulfones 1, only
4-Br (ꢀ)-1c retained the excellent potency of 4-Cl SCH 900229
(ꢀ)-1a. The 4-CF3 substituted analog (ꢀ)-1b also maintained good
potency, while certain analogs with electron deficient groups, such
as 4-CN (1i) and 3,4-difluoro (1e), were somewhat less active. Alk-
oxy substituted analogs (1g and 1h), as well as 3,4-dicyano (1j) and
3,5-difluoro substituted analogs (1f) exhibited more significantly
reduced potency. When dosed orally in mice,18 (ꢀ)-1b and (ꢀ)-
1c demonstrated robust lowering of Ab of both plasma and cortex,
similar to that of compound (ꢀ)-1a. Not surprisingly, the less po-
tent analog (ꢀ)-1i showed a greatly reduced ability to lower Ab
in the same assay.
example, CYP450 IC50 values >10 lM and hERG channel inhibition
of 31% at 10
l
M in a voltage clamp assay. Sulfone (ꢀ)-1b also dis-
played excellent pharmacokinetic properties in rat, monkey and
dog, as shown in Table 3. Compared to (ꢀ)-1a, it has higher expo-
sures, longer half lives in both rat and monkey, and higher oral bio-
availabilities in all the three species.
In summary, SAR development around the two sulfone moieties
of
c
-secretase inhibitor (ꢀ)-1a has been carried out. On the left-
hand side arylsulfone, small substituents, such as 4-Cl, Br, and
CF3 on the aryl ring are well tolerated. Other analogs containing
electron-rich and electron-poor groups, such as 4-OMe and 4-CN,
are much less active. On the right-hand side, an ethylene linker
Table 1
Aryl sulfone substitution SAR data
F
O
O
O
H
O
S
F
S
O
O
1
X
5
3
a,b
a,b
Compound
X
Ab40 IC50 (nM)
Membrane
Ab42 IC50 (nM)
In vivo Ab40c (%)
Plasma
Cell
Cell
Cortex
(ꢀ)-1a
(ꢀ)-1b
(ꢀ)-1c
(ꢀ)-1i
(ꢀ)-1g
(ꢀ)-1h
(ꢀ)-1e
(ꢀ)-1j
(ꢀ)-1f
4-Cl
4-CF3
4-Br
4-CN
4-OMe
4-OCH2CF3
3,4-F,F
3,4-CN,CN
3,5-F,F
1.3
15.0
2.9
4.0
11.0
2.5
25.0
ND
ND
14.0
400
ND
1.0
3.5
0.6
8.9
ND
ND
1.4
120
ND
ꢀ89d
ꢀ75e
ꢀ82e
ꢀ30e
ND
ꢀ78d
ꢀ58e
ꢀ81e
ND
66.0
360
5100
31.0
580
250
ND
ND
ND
ꢀ79e
ꢀ72e
ND
ND
ND
ND
a
b
c
The IC50 data are an average of at least two measurements; the standard deviation was 20%.
Determined in HEKSwe-Lon 293 cells.
Measured at 3 h after oral dosing, (ꢀ) indicates lowering, (+) indicates increase, see Ref. 18.
d
e
These data are from B6C3F1 mice dosed at 30 mg/kg.
These data are from B6C3F1 mice dosed at 10 mg/kg.

848
W.-L. Wu et al. / Bioorg. Med. Chem. Lett. 23 (2013) 844–849
Table 2
Right-hand side chain sulfone substitution SAR data
F
O
O
O
H
O
S
R
F
S
O
O
Cl
In vivo Ab40c (%)
a,b
a,b
Compound
R
Ab40 IC50 (nM)
Ab42 IC50 (nM)
Membrane
Cell
Cell
Plasma
Cortex
(ꢀ)-1a
Me
Et
n-Pr
i-Pr
cyclo-Pr
CF3
CF3CH2
(CH2)2OH
(CH2)3OH
CH2COOH
1.3
3.0
6.8
5.5
2.1
7.4
7.3
1.0
4.5
2.7
4.0
5.0
11.0
8.0
ND
13.0
22.0
1.2
ND
38.0
1.0
2.0
5.0
3.0
ND
4.4
6.4
0.9
ND
22.0
ꢀ89d
ꢀ60d
ꢀ76e
ꢀ2e
ꢀ78d
ꢀ79d
ꢀ61e
ꢀ58e
ꢀ76e
ꢀ18e
ꢀ82e
ꢀ46e
ND
(ꢀ)-16b
(ꢀ)-16c
(ꢀ)-16d
(ꢀ)-16i
(ꢀ)-16a
(ꢀ)-16e
(ꢀ)-16f
(ꢀ)-16g
(ꢀ)-16h
ꢀ77e
ꢀ35e
ꢀ57e
ꢀ42e
ND
+47e
ND
N
(ꢀ)-16j
1.4
1.5
1.8
ꢀ69e
ꢀ56e
HN
N
(ꢀ)-16k
2.1
4.3
8.9
4.7
4.7
+30e
ND
ND
ND
N
HN
N
N
(ꢀ)-16l
13.0
HN
a–e
See Table 1 footnotes.
Table 3
Pharmacokinetic profile of compound (ꢀ)-1ba,b
Species (vehicle)
PO dose (mg/kg)
AUC (0–1) (
3.5
18.0
46.0
l
M h)
Cmax
(l
M)
tmax (h)
t1/2 (h)
F (%)
CL (mL/min/Kg)
40
6.5
4.6
Vd (ss) (L/Kg)
Rat (0.4% MC)
Monkey (40% HPbCD)
Dog (40% HPbCD)
10
5
5
0.68
0.81
1.50
2.0
5.3
2.3
3.6
17.0
17.0
44
70
100
8.9
6.6
6.1
aData are averages from three rats, monkeys, and dogs (n = 3; PO).
bCL and Vd (ss) obtained with iv administration (5 mg/kg for rat, 2.5 mg/kg each for monkey and dog).
A.; Liu, Y.; Lu, Y.; Bhangale, T.; Graham, R. R.; Huttenlocher, J.; Bjornsdottir,
G.; Andreassen, O. A.; Jonsson, E. G.; Palotie, A.; Behrens, T. W.; Magnusson,
O. T.; Kong, A.; Thorsteinsdottir, U.; Watts, R. J.; Stefansson, K. Nature 2012,
488, 96.
between the tricyclic core and sulfone group proved to be optimal
for in vitro and in vivo activity. Many substituents on the right
hand sulfone confer good in vitro potency, and a selected few dem-
onstrated excellent in vivo efficacy and pharmacokinetic proper-
ties. While not progressed as far as SCH 900229, compound (ꢀ)-
1b demonstrated robust in vitro and in vivo efficacy across rodent
species. Pharmacokinetic profiles, including exposure, half-life, and
bioavailability are generally favorable.
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Acknowledgments
The authors would like to thank Lisa Broske’s group for animal
dosing and Sam Wainhaus’ group for the pharmacokinetic sample
analysis. We thank Dr. Birendra Pramanik’s group and Dr. Tse-Ming
Chan’s group for analytical support, and Dr. Jesse Wong, Dr. Xian
Liang and Mr. Yan Jin for scale-up of some key intermediates.
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