Part 3: Notch-sparing γ-secretase inhibitors: SAR studies of 2-substituted aminopyridopyrimidinones

Article abstract of DOI:10.1016/j.bmcl.2016.03.077

In search for novel lead compounds as γ-secretase inhibitors, analogs of aminopyrido[2,3-d]pyrimidin-7-ones (I) were synthesized and evaluated for inhibitory effects on amyloid-β-peptide production and cleavage of the Notch1 receptor mediated by γ-secretase. Selected pyridopyrimidines, such as 1, 8, 9,10, 11 and 16 are γ-secretase inhibitors that did not have an effect on Notch1 receptor processing.

Full text of DOI:10.1016/j.bmcl.2016.03.077

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Part 3: Notch-sparing c-secretase inhibitors: SAR studies
of 2-substituted aminopyridopyrimidinones
Jing Zhang, Dai Lu, Han-Xun Wei, Yongli Gu, Dennis J. Selkoe, Michael S. Wolfe,
⇑
Corinne E. Augelli-Szafran
Laboratory for Experimental Alzheimer Drugs (LEAD), Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, 77 Avenue Louis Pasteur,
Harvard Institutes of Medicine, Boston, MA 02115, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
In search for novel lead compounds as c-secretase inhibitors, analogs of aminopyrido[2,3-d]pyrimidin-7-
ones (I) were synthesized and evaluated for inhibitory effects on amyloid-b-peptide production and
Received 3 January 2016
Revised 21 March 2016
Accepted 22 March 2016
Available online xxxx
cleavage of the Notch1 receptor mediated by -secretase. Selected pyridopyrimidines, such as 1, 8, 9,
c
10, 11 and 16 are
c-secretase inhibitors that did not have an effect on Notch1 receptor processing.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Alzheimer’s disease
c
-Secretase inhibitors
Aminopyridopyrimidines
Notch-processing
Ab production
Alzheimer’s disease (AD) is a progressive and fatal neurodegen-
erative disease that currently affects over 5 million Americans.1 AD
is characterized by slow but progressive impairment in cognition,
behavior and daily-life function. The main pathological hallmarks
of AD are the extracellular deposition of amyloid-b (Ab) peptides
and the formation of intracellular neurofibrillary tangles.2 To date,
treatment of AD involves drugs that can only delay the inevitable
AD symptoms without tackling the main neuropathological causes
of the disease. Scientific advances in understanding AD etiology has
led to the identification of the oligomerization of Ab peptides in the
brain as a key causal factor for AD.3 Accumulation of Ab oligomers
begins in the brain long before the onset of AD as a result of reduced
Ab clearance or increased Ab production.4,5 Ab peptides are pro-
duced from the amyloid precursor protein (APP) through sequential
including intestinal goblet cell hyperplasia, thymus atrophy,
decrease in lymphocytes, and alterations in hair color.10 Our strat-
egy for seeking AD therapeutics has been Notch-sparing gamma-
secretase inhibitors. Greengard and colleagues discovered that Ab
production by
c-secretase in cells is dependent on adenosine
triphosphate (ATP).11 It was reported that compounds such as
GleevecTM (imatinib mesylate) and PD173955 (Fig. 1) compete with
ATP for binding to target kinases and can also inhibit Ab production
by c-secretase with selectivity over the cleavage of Notch1. Coinci-
dentally, both Gleevec and PD173955 incorporate
a phenyl
aminopyrimidine pharmacophore.
Our early screening focus for this series of compounds was eval-
uating permutations at the C-2 pyrimidine position of the template
of PD173955. In Table 1, when R1 is hydrogen (as in PD173955)
and R2 is 4-OCH3-phenyl (1, 47%) and 4-SCH3-phenyl (2, 47%),
overall better activity and selectivity was observed. There also
was no change observed for Notch1 processing for either of these
compounds. Interestingly, the 4-thiomethylphenyl analog (2)
showed Ab40 inhibition whereas the 3-thiomethylphenyl analog
PD173955 (1) showed no Ab40 inhibition. In addition, 4-CF3-phe-
nyl analog (4) showed a significant decrease in activity.
proteolytic cleavages catalyzed by b- and
pressing Ab production by inhibiting -secretase has been proposed
as one of the disease-modifying approaches for AD therapy.7
c
-secretases.6 Hence, sup-
c
c
-Secretase is a protein complex composed of nicastrin, Aph-1,
Pen-2, and either presenilin-1 (PS-1) or presenilin-2 (PS-2).8
Cleavage of Notch receptors, required for their cell signaling, is also
catalyzed by
c
-secretase.9 Interference with Notch receptor
signaling, particularly from Notch1, can lead to severe side effects,
Phenyl and benzyl analogs (3 and 7) and small alkyl (R2 = iso-
propyl, 5) led to decreased or no activity (26%, 0%, 0%, respectively).
However, a longer alkyl chain analog (R2 = n-hexyl, 6) and a
⇑
Corresponding author at present address: Chemistry Department, Drug
Discovery Division, Southern Research, 2000 Ninth Avenue South, Birmingham,
AL 35205, United States. Tel.: +1 205 581 2305.
methylpyridinyl analog (8) showed
a significant increase in
potency (53%, 59%, respectively), with (6) also showing inhibition
of Notch1 processing. Additionally, activity increased substantially
E-mail address: caugelli-szafran@southernresearch.org (C.E. Augelli-Szafran).
http://dx.doi.org/10.1016/j.bmcl.2016.03.077
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
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2
J. Zhang et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
Table 2
N
Cl
2-Piperazinyl-pyridopyrimidin-7-ones
5
4
N
N
NH
N
H
N
3
6
N
N
2
R2
R3
7
Cl
O
S
N
N
1
N
Me
PD173955
O
H
N
6
R2
Imatinib
N
2
N
N
O
N
R1
Figure 1. Structure of Imatinib and PD173955.
(X)
R2 R3
when the hydrogen of (7) was replaced with isopropyl group to
give 10 (0–90%). Good activity of substituted benzyl analogs 11
and 12 (3,4-diCl, 50% and 3,4-diF-, 73%, respectively) was main-
tained, although not as active as the unsubstituted benzyl analog
10 (90%).
Entry R1
Ab40 (%)
Notch1
inhibitiona
processingb
13
4-F-Ph-
H
t-
Bu
Cl
H
H
H
2
n.t.
14
15
16
17
18
19
4-F-Ph-
4-F-Ph-
4-F-Ph-
CH3
H
F
Cl
Cl
H
Cl
0
n.t
Examples of replacing R1 and R2 of (I) with a 4-substituted
piperazine ring are illustrated in Table 2. Activity was increased
significantly with a 4-F-phenyl-substituted piperazine ring (16,
68%) and a 2,6-dichloro-phenyl group at C-6.
20
68
0
14
0
Inhibition
No change
No change
Inhibition
n.t.
4-F-Ph
H
H
2-Tetrahydrofuran-
methyl
Similar to phenyl pyridopyrimidinone 10, this piperazinyl pyri-
dopyrimidinone 16 also had very good Ab40 inhibition. Evaluation
of selected drug-like properties (e.g., solubility, LogD, plasma pro-
tein binding, permeability, and human and rodent microsomal sta-
bility) of each of these two compounds was performed. These
results indicated that 16 had a slightly better drug-like profile
and thus, was further tested in an Ab42 cellular assay along with
other analogs. Pyridopyrimidinone 16 showed inhibition in cells
20
21
22
2-Pyridinyl
Cl
Cl
Cl
H
H
H
0
0
0
n.t.
n.t.
n.t.
2-Pyrimindyl
3-Pyridinyloxyl
a,bSee Table 1 and Refs. 15,20.
n.t. = not tested.
compounds were prepared as shown in Scheme 1. The preparation
of these pyridopyrimidinones typically requires an eight-step syn-
thesis beginning with commercially available 4-chloro-2-thio-
methyl-5-pyrimidine-carboxylate ethyl ester (II) which is first
converted to the corresponding methylamine and then subse-
quently reduced with lithium aluminum hydride to yield alcohol
(III). Oxidation of (III) with manganese oxide gave intermediate
2-thiomethyl-pyrimidine-5-carboxaldehyde (IV). Condensation of
aldehyde (IV) with 2,6-dichlorophenyl-acetonitrile provided pyr-
ido[2,3-d]pyrimidin-7-ylideneamine (V). Acylation of (V) gave 7-
N-acetylimine (VI) which was readily hydrolyzed to yield methyl-
sulfide intermediate (VII). Subsequent oxidation of (VII) with m-
chloro-perbenzoic acid provided sulfonyl pyridopyrimidinone
(VIII). Refluxing (VIII) with selected amines in DMF or neat led to
the production of the desired 2-amino pyridopyrimidinones (I) in
good yields, ranging from 50% (6) to 95% (4).
(Ab42) with an IC50 = 2.7 lM, (see Supplemental data).
Additional piperazinyl pyridopyrimidinone analogs were syn-
thesized as illustrated in Table 2. An unsubstituted phenyl ring
(18, 14%) or other substitutions such as 2,6-diF- (15, 20%), 4-Cl-
(14, 0%), and 4-t-butyl- (13, 2%) on the phenyl ring at C-6 dimin-
ished activity. Additionally, replacing the 4-F-phenyl ring (R1) of
16 with a simple methyl group (17) and with various heterocycles
(19–22) all yielded 0% inhibition of Ab40.
The general synthetic routes to obtain 2-aminopyrido[2,3-d]
pyrimidin-7-one analog (I) are described by several research
teams.12–14 According to these reported methods, some of our
Table 1
2-Amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]-pyrimidin-7-ones
Cl
This original eight-step reported synthesis illustrated in
Scheme 1 worked well, but the route was inconvenient for further
variation on the C-6 position. To simplify the synthesis, we devel-
oped a novel method to prepare key intermediate pyridopyrimidi-
N
6
R1
Cl
N
2
N
N
O
R2
(I)
none (VII) in four steps rather than
5 steps. Methylsulfide
intermediate (VII) was easily obtained by the condensation of 5-
pyrimidinecarboxyaldehyde (IV) with readily available substituted
phenylacetates in DMF in the presence of Cs2CO3 at room temper-
ature or under refluxing conditions. This improved synthetic
method, a total of 6 steps rather than eight steps, was used to pre-
pare compounds 3 and 4 (Table 1) and 13–22 (Table 2).
As a means of reducing the molecular weight of the target pyri-
dopyrimidinone compounds as well as to explore the role of the C-
6 aryl group, compound 23 was synthesized from 8-methyl-2-
(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (IX, Scheme 2).
Pyridopyrimidinone (IX) was prepared from intermediate (IV)
according to a reported method.14
Entry
R1
R2
Ab40 (%)
Notch1
inhibitiona
processingb
PD173955
H
H
H
H
H
H
H
H
H
3-(CH3S)Ph-
4-(CH3O)Ph-
4-(CH3S)Ph-
Ph-
4-(CF3)Ph-
i-Pr
n-Hexyl
PhCH2-
(2-Pyridinyl)
CH2-
0
47
47
26
12
0
53
0
59
No change
No change
No change
n.t.
1
2
3
4
5
6
7
8
n.t.
No change
Inhibition
n.t.
No change
9
CH3 Ph(CH2)2-
i-Pr PhCH2-
i-Pr (3,4-Cl2Ph)CH2- 50
i-Pr (3,5-F2Ph)CH2- 73
48
90
No change
No change
No change
Inhibition
10
11
12
This series of pyridopyrimidinones were evaluated for their
inhibition of
purified human
strate C100Flag.15–21 Effects of these compounds on
c
-secretase-mediated Ab40 production by ELISA using
-secretase complexes and recombinant APP sub-
-secretase-
c
n.t. = not tested.
a,bSee Refs. 15,20.
c
a
Compounds were tested at the concentration of 100
production is a percentage of DMSO control.
Compounds were tested at the concentration of 100 lM. The effects on Notch1
processing are compared to DMSO control; No change: Notch1 processing was not
l
M. The inhibition of Ab40
mediated processing of Notch1 were examined by Western blot
analysis using recombinant substrate N100Flag as previously
reported.21 Compounds with at least a 50% inhibition in the Ab40
ELISA were chosen for evaluation of Notch1 processing.
b
affected by the tested compounds at the concentration of 100 M.
l
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J. Zhang et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
3
(a) aq. MeNH2
CH2OH
COOEt
Cl
N
N
THF
S
N
S
N
NHCH3
(b) LiAlH4
THF
III
II
(c) MnO2
CHCl3
CHO
N
(d) (2,6-Cl2)PhCH2CN
K2CO3, DMF
S
N
IV
NHCH3
(i) Substituted Phenylacetates
Cs2CO3, DMF
rt or reflux
1050C, overnight
Cl
Cl
N
N
Cl
Cl
NH
S
N
N
O
S
N
N
(e) Ac2O
reflux
(f) 6 N HCl
reflux
VII
V
Cl
N
(g) m-CPBA
Cl
NAc
S
N
N
CHCl3
VI
Cl
Cl
N
(h) amine, neat
or reflux in DMF
Cl
N
S
N
N
O
R1
Cl
O
O
N
N
I
N
O
R2
VIII
Scheme 1. Synthesis of 2-amino substituted 6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidinones.
N
O
N
(j) 1-(4-fluorophenyl)-piperazine
S
N
N
Me
O
N
N
N
Me
O
O
N
THF, 60oC, pressure tube
48% yield
IX
F
23
Scheme 2. Synthesis of Compound 23.
Contrary to the previous Letter,11 initial biological studies of
compound PD173955 showed no effect on -secretase-mediated
production of Ab40 at the testing concentration (100 M) in our
assay conditions. Nonetheless, many other 2-amino substituted
pyridopyrimidin-7-ones still displayed the desired Notch-sparing
piperazine ring yielded the most active of these analogs, 16, with
a 68% inhibition of Ab40 production and no change in Notch1 pro-
cessing. Adding molecular weight to the already quite large pyri-
dopyrimidine core was not ideal for solubility and brain
penetration. However, when this 4-F-phenyl group of 16 was
replaced with a 4-methyl group, (17), activity was completely
abolished (0%) as it was also for other 4-aryl groups, such as 2-
tetrahydrofuran methyl (19), 2-pyridinyl (20), 2-pyrimidinyl (21)
and 2-pyridinyloxyl (22). Hence, the 4-F-phenyl group of (16) on
the piperazine ring perhaps could behave like a lipophilic handle
that is able to reach necessary interactions that influence the inhi-
bition of Ab40. Of the various substituents studied for R2 and R3 in
structure (X) (Table 2), 2,6-dichloro-phenyl was preferred and
yielded 68% inhibition (16) of Ab40 production whereas other phe-
nyl substitutions gave slight to no inhibition (15, 2,6-di-F, 20%; 13,
4-t-butyl, 2%; 14, 4-Cl, 0%).
c
l
c-secretase inhibition profiles. For example, the results shown in
Table 1 illustrate reasonable activity of pyridopyrimidinone ana-
logs that have a 4-substituted phenyl ring at C-2 regardless if
R1 = H or a small alkyl group (e.g., 1, 2, 9, 11 and 12, Table 1). How-
ever, the most active compound 10 (90% inhibition of Ab40) has
R1 = isopropyl and an unsubstituted phenyl ring for R2. Compound
10 also had no effect on Notch1 processing. Substitution on the
phenyl ring of 10 with 3,4-diCl and 3,5-diF gave a slight decrease
in activity (11, 50% and 12, 73%, respectively).
The introduction of a cyclic amine such as a 4-substituted piper-
azine yielded novel inhibitors as well as a possible avenue to
improve the drug-like character, e.g., increasing solubility, of these
pyridopyrimidinones. The results showed that the R1 substitution
at the N position of the piperazinyl ring significantly influenced
the inhibitory effects of analogs X (Table 2) on Ab production
Modifications at position 6 of pyridopyrimidinone (X) led to
data (Table 2) that indicated the importance of the 6-(2,6-dichlor-
ophenyl) group for activity. The dichloro-substitution on the phe-
nyl ring also appears to be contributing to Notch selectivity
when coupled with the 4-fluorophenyl piperazine ring (16 com-
mediated by
c-secretase. The 4-F-phenyl substituent on the
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4
J. Zhang et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
Table 3
Center and members of the Center for Neurologic Diseases for fund-
ing support.
2-(4-Fluorophenyl)piperazinyl pyridopyrimidin-7-ones
R
O
N
Supplementary data
N
N
N
N
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2016.03.
077.
F
Entry
R
Ab40 (%) inhibitiona
Notch1 processingb
References and notes
16
23
2,6-Dichlorophenyl
H
68
0
No change
n.t.
1. Alzheimer’s Disease Facts and Figures; Alzheimer’s Association, 2011.
2. Selkoe, D. J. Science 1997, 275, 630.
3. Goedert, M.; Spillantini, M. G. Science 2006, 314, 777.
a,bSee Table 1 and Refs. 15,20.
n.t. = not tested.
4. Golde, T. E.; Schneider, L. S.; Koo, E. H. Neuron 2011, 69, 203.
5. Galimberti, D.; Scarpini, E. Front. Biosci. (School Ed.) 2011, 3, 252.
6. Wolfe, M. S. Neurotherapeutics 2008, 5, 391.
7. Imbimbo, B. P. Curr. Top. Med. Chem. 2008, 8, 54.
8. Selkoe, D. J. Arch. Neurol. 2005, 62, 192.
pared to 15 and 18). Analogs with this same 2,6-dichloro-substitu-
tion pattern (19–22), but with various heterocycles replacing 4-flu-
orophenyl on the piperazine ring showed no activity.
9. Wolfe, M. S. Semin. Cell Dev. Biol. 2009, 20, 219.
10. Panza, F.; Frisardi, V.; Imbimbo, B. P.; Capurso, C.; Logroscino, G.; Sancarlo, D.;
Seripa, D.; Vendemiale, G.; Pilotto, A.; Solfrizzi, V. CNS Neurosci. Ther. 2010, 16,
272.
11. Netzer, W. J.; Dou, F.; Cai, D.; Veach, D.; Jean, S.; Li, Y.; Bornmann, W. G.;
Clarkson, B.; Xu, H.; Greengard, P. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 12444.
12. Klutchko, S. R.; Hamby, J. M.; Boschelli, D. H.; Wu, Z.; Kraker, A. J.; Amar, A. M.;
Hartl, B. G.; Shen, C.; Klohs, W. D.; Steinkampf, R. W.; Driscoll, D. L.; Nelson, J.
M.; Elliott, W. L.; Roberts, B. J.; Stoner, C. L.; Vincent, P. W.; Dykes, D. J.; Panek,
R. L.; Lu, G. H.; Major, T. C.; Dahring, T. K.; Hallak, H.; Bradford, L. A.; Showalter,
H. D.; Doherty, A. M. J. Med. Chem. 1998, 41, 3276.
13. Hamby, J. M.; Connolly, C. J.; Schroeder, M. C.; Winters, R. T.; Showalter, H. D.;
Panek, R. L.; Major, T. C.; Olsewski, B.; Ryan, M. J.; Dahring, T.; Lu, G. H.; Keiser,
J.; Amar, A.; Shen, C.; Kraker, A. J.; Slintak, V.; Nelson, J. M.; Fry, D. W.; Bradford,
L.; Hallak, H.; Doherty, A. M. J. Med. Chem. 1997, 40, 2296.
14. Barvian, M.; Boschelli, D. H.; Cossrow, J.; Dobrusin, E.; Fattaey, A.; Fritsch, A.;
Fry, D.; Harvey, P.; Keller, P.; Garrett, M.; La, F.; Leopold, W.; McNamara, D.;
Quin, M.; Trumpp-Kallmeyer, S.; Toogood, P.; Wu, Z.; Zhang, E. J. Med. Chem.
2000, 43, 4606.
Interestingly, since 15 and 18 each have the 4-F-piperazinyl
substituent at R1, but do not have 2,6-dichloro phenyl at C-6, it is
speculated that perhaps the substitution pattern on the C-6 aryl
ring (R2 and R3) could be influencing the Notch selectivity of the
pyridopyrimidine analog since both compounds inhibited Notch.
The dihedral angle between the phenyl ring and the pyridopyrim-
idinone template may be important for Notch1-sparing activity. If
so, then it appears that the dihedral angle generated with the 2,6-
dichlorophenyl group in 16 (i.e., in which a coplanar orientation
would be excluded) is preferred for both Ab inhibition and
Notch1-sparing selectivity over that of an unsubstituted phenyl
or 2,6-F-phenyl ring (18 and 15, respectively). When the 6-(2,6-
dichlorophenyl) group of 16 was completely removed to give 23,
inhibition of Ab production mediated by
c-secretase was com-
15. Ab ELISA: The proteolytic reaction mixtures contained C100 FLAG substrate and
pletely lost (Table 3). This may indicate that in addition to the
2,6-dichloro-phenyl group of 16 being important for Notch selec-
tivity, a bulky aryl group such as this at C-6 is also necessary for
Ab40 inhibition.
purified
solutions of the tested compounds in DMSO were prepared. The drug
concentration in the reaction buffer was 100 M, with a final DMSO concen-
c
-secretase complex in 0.2% CHAPSO/HEPES at pH 7.5.15–17 Stock
l
tration of 1%. After incubation at 37 °C for 4 h, all reactions were stopped by
adding 0.5% SDS, and the samples were assayed for Ab40 by a specific ELISA
(Invitrogen).
In summary, Notch-sparing inhibition of
c-secretase can be
16. Fraering, P. C.; Ye, W.; Strub, J. M.; Dolios, G.; LaVoie, M. J.; Ostaszewski, B. L.;
van Dorsselaer, A.; Wang, R.; Selkoe, D. J.; Wolfe, M. S. Biochemistry 2004, 43,
9774.
17. Esler, W. P.; Kimberly, W. T.; Ostaszewski, B. L.; Ye, W.; Diehl, T. S.; Selkoe, D. J.;
Wolfe, M. S. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 2720.
18. Kimberly, W. T.; Esler, W. P.; Ye, W.; Ostaszewski, B. L.; Gao, J.; Diehl, T.; Selkoe,
D. J.; Wolfe, M. S. Biochemistry 2003, 42, 137.
19. Xia, W.; Zhang, J.; Ostaszewski, B. L.; Kimberly, W. T.; Seubert, P.; Koo, E. H.;
Shen, J.; Selkoe, D. J. Biochemistry 1998, 37, 16465.
achieved from molecules bearing the 6-(2,6-dichlorophenyl)-pyr-
ido[2,3-d]pyrimidin-7-one motif. The data obtained in this study
indicates the possibility that a dihedral angle between the plane
of C-6-aryl and the pyridopyrimidinone template could influence
the Notch-sparing property of these types of molecules. The inhibi-
tory activity of these compounds was significantly affected by a
substituted piperazinyl moiety at C-2 of the pyrido[2,3-d]pyrim-
idin-7-one core. These findings could facilitate further design and
20. Western blot analysis: 18 compounds showing Ab inhibition at about 50% from
the c-secretase activity assays were selected and run on 10 20% Tris–Tricine
synthesis of this series of Notch-sparing c-secretase inhibitors.
gels (Bio-Rad) or 4–20% Tris–glycine gels (Invitrogen) and transferred to
polyvinylidene difluoride membranes to detect AICD FLAG (when C100Flag
was substrate) with anti-FLAG M2 antibodies (1:1000, Sigma) or NICD-FLAG
(when N100Flag was substrate) with FLAG (when C100Flag was substrate)
with anti-FLAG M2 antibodies cleaved Notch1 (Val1744) antibody (1:1000, Cell
Signaling Technology) that is selective for the N-terminus of NICD.
21. Fraering, P. C.; Ye, W.; LaVoie, M. J.; Ostaszewski, B. L.; Selkoe, D. J.; Wolfe, M. S.
J. Biol. Chem. 2005, 280, 41987.
Acknowledgments
We acknowledge Jian Chen and Katherine M. Brogan for their
assistance with the biological testing. We acknowledge the
Alzheimer Drug Discovery Foundation, the Harvard NeuroDiscovery
Please cite this article in press as: Zhang, J.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.03.077