Discovery of a novel series of Notch-sparing γ-secretase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2008.05.064

Using a cell-based assay, we have identified a new series of Notch-sparing γ-secretase inhibitors from HTS screening leads 2a and 2e. Lead optimization studies led to the discovery of analog 8e with improved γ-secretase inhibitory potency and Notch-sparing selectivity.

Full text of DOI:10.1016/j.bmcl.2008.05.064

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4232–4236
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of a novel series of Notch-sparing c-secretase inhibitors
a
b
b
d
a
Anthony Kreft a, , Boyd Harrison , Suzan Aschmies , Kevin Atchison , David Casebier , Derek C. Cole ,
George Diamantidis a, John Ellingboe a, Diane Hauze a, Yun Hu b, Donna Huryn a, Mei Jin b, Dennis Kubrak a,
Peimin Lu b, Joseph Lundquist a, Charles Mann a, Robert Martone b, William Moore d, Aram Oganesian c,
Alex Porte a, Dave R. Riddell b, June Sonnenberg-Reines b, Joseph R. Stock a, Shaiu-Ching Sun b, Erik Wagner b,
Kevin Woller d, Zheng Xu b, Hua Zhou b, J. Steven Jacobsen b
*
a Chemical and Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA
b Discovery Neuroscience, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA
c Drug Safety and Metabolism, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA
d ArQule, Inc., 19 Presidential Way, Woburn, MA 01801, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Using a cell-based assay, we have identified a new series of Notch-sparing c-secretase inhibitors from
HTS screening leads 2a and 2e. Lead optimization studies led to the discovery of analog 8e with improved
Received 29 February 2008
Revised 14 May 2008
Accepted 15 May 2008
Available online 20 May 2008
c
-secretase inhibitory potency and Notch-sparing selectivity.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Alzheimer’s disease
c
-Secretase
Notch
Amyloid
Protease inhibitor
Alzheimer’s disease (AD), the most common form of dementia,
is the biggest unmet medical need in neurology due to the lack
of disease-modifying anti-Alzheimer’s drugs (DMAADs).1,2 Because
the incidence of AD increases with age and our population is
increasing in longevity, the levels of AD are already approaching
epidemic levels.3 Unless new therapies are found that block or de-
lay the progression of AD, the anticipated burden on caregivers and
society threatens to overwhelm available resources.4
fects such as Notch-related G.I. toxicity and effects on T-cell
differentiation.10
O
O
OEt
N
H
O
N
O
S
O
One of the major hopes for a DMAAD is to target the putative AD
pathogens Ab40 and Ab42 either by blocking their synthesis (from
their precursor APP), their aggregation (required for toxicity), or
alternatively accelerating their degradation or clearance.5 An enor-
mous effort is underway to discover inhibitors of the Ab40 and
Cl
N
S
O
O
OH
Cl
1a (EC50Αβ40 = 85 nM)
Cl
1 (EC50Αβ40 = 12,200 nM)
Ab42 biosynthetic enzymes BACE and
the identification of -secretase inhibitors (GSIs) as potential DMA-
ADs has been made more difficult not only by the lack of an X-ray
structure of
-secretase,8,9 but also by the subsequent discovery of
a multitude of other -secretase substrates such as Notch and the
c
-secretase.6,7 However,
c
Recently, we have reported11 on the discovery of novel GSIs as
exemplified by 1 (EC50Ab40 = 12,200 nM) based on molecular mod-
elingof theGSI 1a.12 Compound1awas ofparticularinterestbecause
it not only was a potent GSI (EC50 Ab40 = 85 nM in CHO cells stably
expressing a wild-type recombinant human APP),11 but also exhib-
ited promising Notch-sparing selectivity (EC50Notch = 746 nM,
Notch-sparing selectivity = 8.8).13 As with any other novel drug
class, one needs to define a therapeutic window, which allows some
c
c
resulting concerns about selectivity and mechanism-based side ef-
* Corresponding author. Tel.: +1 732 274 4456; fax: +1 732 274 4505.
E-mail address: krefta@wyeth.com (A. Kreft).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.05.064

A. Kreft et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4232–4236
4233
c
-secretase activity for Notch signaling but reduces Ab40 and Ab42
In this letter, we will present the SAR of these initial leads with
the goals of improving GSI inhibitory potency and Notch-sparing
selectivity.
Our first attempts to improve the GSI potency of the initial leads
2a and 2e were to vary the substitution on the benzene ring and
the sulfonamide linker. Compounds 2a–2r and 3a–3e were pre-
pared by reaction of the b-amino alcohol 4 with the requisite acid
chloride, isocyanate, or benzyl chloride (Scheme 1).
Variation of the para substituent on the phenyl ring revealed
that potency was not retained when halogen was replaced by
non-halogen substituents other than hydrogen or acetyl (com-
pounds 2a, 2r vs 2d–2l, Table 1). Exploration of the position of
the halogen substituent revealed that para-substitution was pre-
ferred (compounds 2a–2c, Table 1). Di-substituted halogen analogs
were less potent in Ab-lowering activity than the parent compound
2a (compounds 2m–2q, Table 1).
Replacement of the SO2 in 2a by other linkers afforded 3a–3e
(Table 2), which were weakly active, at best (EC50Ab >
100,000 nM).
Alkylation of the sulfonamide nitrogen of 2a with MeI/K2CO3 in
DMF gave 5 (Scheme 2) which was almost an order of magnitude
less potent (EC50Ab40 = 5449 and 46,710 nM, respectively).
The preferred chirality of the s-butyl side chain at the carbon
bearing the sulfonamide nitrogen in 2a was found to be the S abso-
lute configuration since 6, the enantiomer of 2a, had significantly
generation significantly enough to affect AD disease progression.14
A successful example of this approach of partial enzyme inhibition
is the use of statins for blocking cholesterol biosynthesis without
mechanism-based side effects.15 The fact that an increase as small
as 30% in the levels of Ab42 can cause familial AD suggests that low-
ering Ab42 by a similar amount could have a disease-modifying ef-
fect.16–18 It has been reported in several recent publications that
the GSI BMS-299897 (EC50Ab40 = 7 nM) which has 15-fold Notch-
sparingselectivitydidnotcauseNotch-relatedG.I. toxicityandunto-
ward effects on T-cell differentiation seen with nonselective GSIs
such as the clinical compound LY45013920 (EC50Ab40 = 28 nM,
Notch-sparing
selectivity = 2.3)
and
BMS-433796
(EC50
Ab40 = 0.3 nM, Notch-sparing selectivity = 0.5).21 This suggests that
this degree of Notch-sparing selectivity may be sufficient to avoid
mechanism-based toxicity.19,22–24 Unfortunately, BMS-299897 it-
self has been shown to induce its own metabolism and subsequently
loses in vivo efficacy over time.19 However,the demonstration that
BMS-299897canlower brain Ab40 and Ab42levels in animalmodels
without Notch-related side effects encouraged us to continue to pur-
sue novel GSIs that would possess this Notch-sparing selectivity
profile.18,25
F
F
OH
HN
O
OH
O
N
O
S
O
N
F
O
NH
OH
Z
OH
H
O
LY450139
Cl
EC50Αβ40 = 28 nM
a
2.3-fold Notch-sparing
BMS-299897
N
N
EC50Αβ40 = 7 nM
15-fold Notch-sparing
Q
H
R
4
2a-2r, 3a-3e
Scheme 1. Reagents: For Q = SO2, CO, CH2, COCH2, CONH and Z = H. (a) RQCI or
RNCO, Et3N or EtN(i-Pr)2, THF or DCM. For Q = SO2NH2 and Z = FMOC: (a) Trityl
resin/AgOTf followed by subsequent reaction with piperidine; RNH2, pNO2PhOS-
O2CI, EtN(i-Pr)2, TFA, DCM.
F
HN
OH
N
N
O
O
NH
F
O
BMS-433796
EC50Αβ40 = 0.3 nM
0.5-fold Notch-sparing
Table 1
SAR of the phenylsulfonamide substitution
HO
R1
O
Because we were unable to significantly improve upon the
in vitro Ab-lowering potency of 1 (EC50Ab40 = 12,200 nM), we
turned to HTS screening of the combined Wyeth and ArQule com-
pound collections as an alternate approach to the discovery of no-
vel Notch-sparing GSIs. This approach afforded the two related
leads 2a, X = Cl and 2e, X = Br (EC50Ab40 = 5449 and 2214 nM,
respectively) utilizing our cell-based assay.11 These leads were
established as GSIs by virtue of their ability to elevate b-CTF levels
using a human APP reporter construct containing the Swedish KM
to NL mutation.11 Encouragingly, both 2a and 2e exhibited promis-
ing Notch-sparing selectivity Table 5 (EC50 Notch = 20,000 nM and
20,000 nM, Notch-sparing selectivity = 3.7 and 9.0, respectively).
N
H
S
O
R2
R5
R3
R4
Compound
R1
R2
R3
R4
R5
Ab40EC50 (nM)
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
Cl
H
Cl
H
H
Cl
H
H
H
H
H
H
H
H
H
H
Cl
F
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
5449
18,304
56,619
4243
F
Br
CN
CH3
CF3
COCH3
2214
>100,000
14,292
13,053
6021
>100,000
20,903
23,532
37,002
7840
OH
SO2CH3
NO2
OCF3
Cl
O
N
H
S
Cl
H
H
H
O
Cl
Cl
H
H
4274
23,496
54,808
4145
X
2a (X = Cl: EC50Αβ40 = 5449 nM)
2e (X = Br: EC50Αβ40 = 2214 nM)
H
LY450139
28

4234
A. Kreft et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4232–4236
Table 2
SAR of the SO2 replacement
R6
OH
OH
H
R6
R8
R8
R7
O
R7
a
HO
N
N
H
H
H
N
H
H
X
H
9
10
H
Cl
b
c
H
R6
Compound
X
Ab40EC50 (nM)
R6
OH
H
OH
H
R8
R7
R8
R7
2a
3a
3b
3c
3d
3e
SO2
SO2NH
CO
CH2
COCH2
CONH
5449
>30,000
>100,000
>100,000
>100,000
47,313
O
a
O
O
N
N
S
S
O
O
Cl
Cl
7, 8h
11
OH
OH
Scheme 3. Reagents: (a) LiAlH4, THF; (b) p-Cl-PhSO2Cl, aq MeCN, Et3N; (c) p-Cl-
PhSO2Cl, THF, Et3N.
O
N
O
S
a
N
H
S
O
O
O
O
O
N
Cl
Cl
O
a, b
O
HO
5
2a
Scheme 2. Reagents: (a) MeI, K2CO3, DMF.
NLi
O
12
13
reduced activity in lowering Ab40 production (EC50Ab >
c,d,e,f
100,000 nM). This is consistent with a stereospecific interaction
with the
c
-secretase complex.
OH
H
OH
OH
OH
O
g
N
S
N
O
S
O
N
O
H
H
N
H
H
S
O
O
Cl
14
8e
Cl
Cl
6
7
Scheme 4. Reagents: (a) t-BuCOCl, Et3N, THF; (b) Li 4-(R)-4-benzyl-2-oxazolidi-
none; (c) EtMgBr, CuBr-DMS, THF; (d) NBS,THF; (e) TMGN3, MeCN; (f) LiAlH4, THF;
(g) p-Cl-PhSO2Cl, Et3N, THF.
Interestingly, 7, the analog with the 2-S, 3-R stereochemistry,
was found to be somewhat more potent than 2a which has the
2-S, 3-S stereochemistry (EC50Ab40 = 758 nM and 5449 nM,
respectively). For preparation of side chain analogs 8a–d and 8f,
the method of Scheme 1 was used substituting the requisite com-
mercially available amino alcohol for S-isoleucinol (4, Z = H). For
preparation of side chain analogs 7 and 8h, we employed two
routes when the requisite amino alcohol was not commercially
Replacement of the s-butyl group in 2a by other side chains (Ta-
ble 3, compounds 8a–8h) improved GSI potency if the side chain
was branched at the b position and the branches were longer than
methyl (e.g. 8e). Cyclization of the side chain led to the less active
analog 8g. Aromatizing the side chain led to 8h which had a further
loss in GSI potency.
Attachment of one or two methyl groups to the carbon bearing
the hydroxyl group resulted in a significant loss of GSI potency (Ta-
ble 4, compounds 15a–15b). The secondary alcohol 15a (as a mix-
ture of diastereomers) was prepared by oxidation of 2a with PCC to
afford the aldehyde 16 followed by reaction with methylmagne-
sium bromide (Scheme 5). The tertiary alcohol 15b was prepared
by conversion of 17, S-isoleucine methyl ester, to the intermediate
18 followed by reaction with methylmagnesium bromide (Scheme
5).
available: (1) reduction of the
amino alcohol 10 followed by sulfonylation to yield 7 and 8h, or (2)
sulfonylation of the -amino acid 9 (or its methyl ester) to afford
a-amino acid 9 to the corresponding
a
11 followed by reduction to provide 7 and 8h (Scheme 3).
For preparation of the side chain analog 8e derived from an
unnatural a-amino acid whose related amino alcohol or acid was
not commercially available we utilized chemistry first developed
by Hruby26 employing an Evans chiral auxiliary (Scheme 4). The
unsaturated acid 12 was first converted to the imide 13, which
was subsequently reacted with the relevant Grignard reagent in
the presence of cuprous ion. Trapping of the resultant enolate with
NBS, displacement of the bromide with azide anion followed by
reduction with LiAlH4 gave the b-amino alcohol 14 which upon
sulfonylation afforded the target compound 8e.
A free hydroxyl group was important for GSI activity. The
methyl ether 19 prepared from 2a (by sequential action of TsCl/
pyr, followed by NaO t-Bu/MeOH/THF) had significantly reduced
Ab-lowering activity (EC50Ab40 > 100,000 nM). Interestingly, the
aldehyde 1627 and methyl ester 18 (prepared as in Scheme 5) were
active although weaker in potency compared to 2a (EC50Ab40 =

A. Kreft et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4232–4236
4235
Table 3
SAR of the side chain
O
R6
MeO
HO
R8
R7
O
S
O
S
N
H
N
HO
H
O
O
O
N
H
H
S
O
H
Cl
Cl
19
20
H
Cl
H
Compound
R6
R7
R8
Ab40EC50 (nM)
It is interesting to compare the results of our SAR on 2a with the
structural features present in 1a and BMS-299897. In contrast to 1a
and BMS-299897 which have the R absolute configuration at the b-
amino alcohol-derived chiral center, we have found that in our ser-
ies, compounds with the R absolute configuration at the b-amino
alcohol-derived chiral center are much less active than the corre-
sponding S enantiomers with respect to GSI activity.
In contrast to 1a which has a masked hydroxyl, we have found
that in our series a free hydroxyl is important for GSI activity. In
contrast to 1a and BMS-299897 which have a small alkyl side
chain, we have found that in our series a large b-branched side
chain is important for potent GSI activity. In contrast to 1a and
BMS-299897, which have an alkylated sulfonamide nitrogen, we
have found that in our series an unalkylated sulfonamide nitrogen
is important for good GSI activity.
With the initial SAR to improve Ab-lowering potency com-
pleted, we next turned to evaluation of the Notch-sparing selectiv-
ity of selected compounds (Table 5). We were gratified to find that
8e not only had improved Ab-lowering potency but also had in-
creased Notch-sparing selectivity relative to our initial lead 2a.
The Notch-sparing selectivity of 8e is comparable to the pub-
lished19 Notch-sparing selectivity of BMS-299897. This is in con-
trast to LY450139 that had very low Notch-sparing selectivity.
8a
8b
8c
8d
2a
7
8e
8f
8g
8h
H
CH3
CH3
CH3
H
H
CH3
CH3
CH3 (S)
CH3 (R)
CH3CH2
H
H
H
H
CH3
H
H
H
H
H
>100,000
>100,000
4575
29,108
5449
758
294
15,279
1122
68,843
CH3CH2
CH3CH2
CH3CH2
(CH3)2CH
R6 + R7 = cyclohexyl
R6 + R7 + R8 = phenyl
Table 4
SAR of substitution on carbon bearing hydroxyl group
R9 R10
HO
O
H
N
H
S
O
H
H
Cl
H
Compound
R9
R10
Ab40EC50 (nM)
2a
15a
15b
H
CH3
CH3
H
H
CH3
5449
49,266
>100,000
Table 5
Notch-sparing selectivity of selected GSIs
Compound
Ab40EC50 (nM)
NotchEC50 (nM)13
Notch-sparing selectivity13
1
2a
2e
8e
85
746
20,000
20,000
4086
8.8
3.7
9
13.9
2.3
5449
2214
294
28
7859, 64,947 and 5449 nM, respectively). However, the related
acid 20 (prepared as in Scheme 3) had significantly reduced Ab-
lowering activity (EC50Ab > 100,000 nM).
LY450139
63
OH
O
OH
H
O
b
a
O
O
N
N
N
H
S
H
S
H
S
O
O
O
Cl
Cl
Cl
2a
16
15a
OH
H
O
O
MeO
MeO
O
S
O
S
c
d
N
N
N
H
H
H
O
O
Cl
Cl
17
18
15b
Scheme 5. Reagents: (a) PCC, DCM; (b) MeMgBr, THF; (c) p-Cl-PhSO2Cl, Et3N, MeCN; (d) MeMgBr, THF.

4236
A. Kreft et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4232–4236
13. For the Notch assay, CHO cells were transfected with the constitutively active
mouse Notch construct Notch which when cleaved by -secretase
In summary, we have improved the potency of HTS leads 2a and
D
E
c
2e by sequential modification of six regions of the molecule. Out of
this SAR effort 8e emerged which had ꢀ14-fold selectivity for APP
cleavage relative to Notch cleavage. This novel GSI scaffold with
improved Notch-sparing selectivity represents an advance over
clinical GSIs such as LY45013920 that do not possess this degree
of Notch-sparing selectivity. Further optimization of this new ser-
ies to identify a clinical candidate is in progress.
transactivates a soluble alkaline phosphatase reporter system. Notch-sparing
selectivity = EC50Notch assay/EC50Ab40. Note that, in general, EC50 values for
Ab40 and Ab42 were similar but because ten times more Ab40 is produced
than Ab42, the EC50Ab40 values were used for SAR purposes.
14. Haass, C. EMBO J. 2004, 23, 483.
15. Kimberly, W.; Wolfe, M. J. Neurosci. Res. 2003, 74, 353.
16. Selkoe, D. Ann. Intern. Med. 2004, 140, 627.
17. Golde, T. J. Clin. Invest. 2003, 111, 11.
18. An alternative to
c-secretase inhibition, which lowers total Ab levels, is c-
secretase modulation which does not lower total Ab levels but rather
selectively lowers the more toxic Ab42 levels by shifting the site of cleavage
by c-secretase. These c-secretase modulators (GSMs) are claimed to not affect
Acknowledgments
Notch cleavage. One of these GSMs, R-flurbiprofen, is in Phase 3 AD clinical
trials. For recent reviews on GSMs see (a) Schmidt, B.; Baumann, S.; Braun, H.
A.; Larbig, G. Curr. Top. Med. Chem. 2006, 6, 377; (b) Czirr, E.; Weggen, S.
Neurodegen. Dis. 2006, 3, 298; (c) Leuchtenberger, S.; Beher, D.; Weggen, S. Curr.
Pharm. Design 2006, 12, 4337.
The authors thank Dr. Magid Abou-Gharbia for his support,
encouragement and leadership and Dr. Gregory Welmaker for his
contributions in analyzing the HTS data.
19. (a) 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; (b) Anderson, J. J.; Holtz, G.; Baskin, P. P.; Turner, M.;
Rowe, B.; Wang, B.; Kounnas, M. Z.; Lamb, B. T.; Barten, D.; Felsenstein, K.;
McDonald, I.; Srinivasan, K.; Munoz, B.; Wagner, S. L. Biochem. Pharmacol.
2005, 69, 689.
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24. Note that the safety of a compound is also dependent on drug disposition
in vivo (e.g.
a GSI with Notch-sparing selectivity of 100 may be more
peripherally toxic than a GSI of comparable potency and with Notch-sparing
selectivity of 15 if the former compound has poor brain penetration and the
latter compound has high brain penetration).
25. Note that Notch-nonselective clinical GSIs may have therapeutic potential in
oncology due to the involvement of Notch processing in certain cancers. For a
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rat, mouse or human microsomes.
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