Novel pyrrolyl 2-aminopyridines as potent and selective human β-secretase (BACE1) inhibitors

Article abstract of DOI:10.1016/j.bmcl.2010.02.075

The proteolytic enzyme β-secretase (BACE1) plays a central role in the synthesis of the pathogenic β-amyloid in Alzheimer's disease. Recently, we reported small molecule acylguanidines as potent BACE1 inhibitors. However, many of these acylguanidines have a high polar surface area (e.g. as measured by the topological polar surface area or TPSA), which is unfavorable for crossing the blood-brain barrier. Herein, we describe the identification of the 2-aminopyridine moiety as a bioisosteric replacement of the acylguanidine moiety, which resulted in inhibitors with lower TPSA values and superior brain penetration. X-ray crystallographic studies indicated that the 2-aminopyridine moiety interacts directly with the catalytic aspartic acids Asp32 and Asp228 via a hydrogen-bonding network.

Full text of DOI:10.1016/j.bmcl.2010.02.075

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2068–2073
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel pyrrolyl 2-aminopyridines as potent and selective human b-secretase
(BACE1) inhibitors
b
b
b
a
a
Michael S. Malamas a, , Keith Barnes , Yu Hui , Matthew Johnson , Frank Lovering , Jeff Condon ,
William Fobare a, William Solvibile a, Jim Turner c, Yun Hu c, Eric S. Manas a, , Kristi Fan a, Andrea Olland d,
Rajiv Chopra d, Jonathan Bard c, Menelas N. Pangalos c, Peter Reinhart c, Albert J. Robichaud a
*
a Department of Chemical Sciences, Wyeth, CN 8000, Princeton, NJ 08543-8000, USA
b Albany Molecular Research, Albany, NY, USA
c Neuroscience, Wyeth, CN 8000, Princeton, NJ 08543-8000, USA
d Department of Chemical Sciences, Wyeth, 200 Cambridge Park Drive, Cambridge, MA 02140, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The proteolytic enzyme b-secretase (BACE1) plays a central role in the synthesis of the pathogenic b-amy-
loid in Alzheimer’s disease. Recently, we reported small molecule acylguanidines as potent BACE1 inhib-
itors. However, many of these acylguanidines have a high polar surface area (e.g. as measured by the
topological polar surface area or TPSA), which is unfavorable for crossing the blood–brain barrier. Herein,
we describe the identification of the 2-aminopyridine moiety as a bioisosteric replacement of the acyl-
guanidine moiety, which resulted in inhibitors with lower TPSA values and superior brain penetration.
X-ray crystallographic studies indicated that the 2-aminopyridine moiety interacts directly with the cat-
alytic aspartic acids Asp32 and Asp228 via a hydrogen-bonding network.
Received 12 January 2010
Revised 14 February 2010
Accepted 18 February 2010
Available online 23 February 2010
Keywords:
Alzheimer’s disease (AD)
BACE1 inhibitors
Beta-amyloid peptide (Ab)
2-Aminopyridines
Ó 2010 Elsevier Ltd. All rights reserved.
Alzheimer’s disease (AD)à is a progressive, degenerative disease
of the brain and recognized as the leading cause of dementia in
the aging population. The prognosis of AD is poor and there is a great
need for medical intervention of this disease. Currently, the ap-
proved medical therapies consist of cholinesterase inhibitors and
N-methyl D-aspartate (NMDA) antagonists, that reduce the symp-
tomatology of the disease in the initial phase, but do not appear to
be capable of curing or stopping its progression.1,2 The pathological
hallmarks of AD include the aggregation and extracellular deposition
of b-amyloid peptide (Ab), which leads to plaque formation, and the
abnormal hyperphosphorylation of tau protein, which leads to the
intracellular formation of neurofibrillary tangles.3,4 b-amyloid
deposits are predominately aggregates of the Ab peptides (Ab, 39–
43 residues) resulting from the endoproteolysis of the amyloid pre-
cursor protein (APP).5,6 These peptide fragments result from the
sequential cleavage of APP, first at the N-terminus by b-secretase en-
zyme (b-site APP cleaving enzyme, BACE1),7–13 followed at the C-ter-
minus by one or more
c-secretase complexes (intramembrane
aspartyl proteases),10 as part of the b-amyloidogenic pathway.
Although the cause of AD remains unknown, a large body of evi-
dence is beginning to accumulate that highlights the central role of
Ab in the pathogenesis of the disease.11–13 Thus, processes that limit
Ab production and deposition by preventing formation, inhibiting
aggregation, and/or enhancing clearance may offer effective treat-
ments for AD. Since b-secretase mediated cleavage of APP is the first
and rate-limiting step of the amyloidogenic processing pathway,
BACE1 inhibition is considered a prominent therapeutic target for
treating AD by diminishing Ab peptide formation in AD patients.
We report herein the design and synthesis of novel pyrrolyl 2-
aminopyridines as BACE1 inhibitors. This work is an extension of
our previously reported acylguanidines BACE1 inhibitors14 1. The
acylguanidine inhibitors are polar compounds, particularly due to
the acylguanidine moiety, as suggested by the high total polar sur-
face area (TPSA), which we hypothesized was leading to the ob-
served poor blood–brain barrier permeation (<5%). The objective
of our studies is to modify the acylguanidine moiety, effectively re-
duce TPSA and thus improve compound permeability. Molecular
modeling studies have suggested that the aminopyridine moiety
(2; Fig. 1) could replace the acylguanidine moiety, bind satisfacto-
* Corresponding author.
E-mail address: malamas.michael@gmail.com (M.S. Malamas).
Present address: Department of Computational and Structural Chemistry, Glaxo-
SmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA.
à
Abbreviations. AD, Alzheimer’s disease; Ab, beta-amyloid peptide, APP, b-amyloid
precursor protein; BACE, b-site APP cleaving enzyme; FRET, fluorescence resonance
energy transfer; ELISA, enzyme-linked immune sandwich assay; CHO, Chinese
hamster ovary. Atomic coordinates of the BACE1 crystal structure with compounds
32 (3L3A) and 44 (3L38) have been deposited in the Protein Data Bank, Research
Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, New
Jersey.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.02.075

M. S. Malamas et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2068–2073
2069
rily to the bis-aspartate warhead, and also decrease the TPSA of the
O
O
molecule. Furthermore, potentiometric pKa measurements of a ser-
ies of acylguanidines and related analogs (unpublished data) sug-
gested that the ideal pKa range for the acylguanidine mimetic
would be 6–7, making 2-aminopyridine (pKa = 6.86) within the
appropriate range. Recently, aminoheterocycles as BACE1 inhibitor
have also been disclosed.15 The synthesis and SAR evaluation of the
aminopyridines as BACE1 inhibitors will be the central focus of this
paper. The X-ray crystallographic studies of the aminopyridines
complexed with the BACE1 enzyme, which showed that the 2-ami-
nopyridine moiety directly interacts with the catalytic aspartic
acids Asp32 and Asp228 via a hydrogen-bonding network as in-
tended, will also be discussed.
NH2
NH2
N
N
b
a
c, d
N
N
O
O
N
N
H2N
14
15
16
6
Br
O
O
O
NO2
NO2
c, d
NO2
b
N
N
N
H2N
Br
17
18
7
Scheme 2. Reagents: (a) phthalic anhydride, AcOH; (b) NBS AlBN, CCl4; (c)
The compounds needed to delineate the SAR for this study were
prepared according to synthetic Schemes 1 and 319. The 1,4-diary-
lbutane-1,4-diones (5; Scheme 1) were prepared according to
Kulinkovich’s synthetic protocol18 in a one-step cross coupling-
reaction of ketones 3 and 4 in the presence of ZnCl2. These
diketones were treated with amines 6 and 7 to produce the
corresponding pyrroles 8 and 11, respectively. Demethylation of
pyrrole 8 with boron tribromide furnished phenol 9, which upon
treatment with cesium carbonate and alkyl iodides produced alter-
nately substituted ethers 10. Alkyl-hydroxyl analogs 12 and 13
were prepared by two different synthetic routes from the common
pyrrole intermediate 11. In route a, pyrrole 11 was first treated
with ethanolamine and subsequently with iron metal to furnish
aminopyridines 12 (X = NH). In route b, the initial demethylation
of the methoxy group of 11 was followed by alkylation and reduc-
tion with iron metal to produce aminopyridines 13 (X = O-alkyl).
The required starting amines for these assemblies, 6 and 7 were
prepared according to Scheme 2. Treatment of amino-pyridine 14
with phthalic anhydride produced imide 15, which was bromi-
nated to furnish benzyl bromide 16. Reaction of 16 with potassium
potassium phthalimide; (d) hydrazine, EtOH.
phthalimide and subsequent hydrolysis with hydrazine furnished
amine 6. Amine 7 was prepared in a similar process as that of 6
starting from pyridine 17. The 5-oxo-pyrimidinyl analogs 22 and
ethanolamines 23 were prepared according to Scheme 3, from ke-
tones 20 and 21. Ketone 20 was prepared from 4-fluoroacetophe-
none 19 upon treatment with 5-hydroxyl pyrimidine. Amides 26
were prepared from 24 (prepared according to Kulinkovich’s syn-
thetic protocol18) by initially generating the acyl chloride that then
followed by amide formation and cyclization to pyrrole as de-
scribed in Scheme 1.
We have previously reported14 the SAR studies of the acylgua-
nidine series 1, where the initial HTS hit 1 was rapidly optimized
by using structure-based drug design techniques. While this class
of inhibitors demonstrated excellent potency for the BACE1 en-
zyme (IC50 ꢀ50 nM), we felt that the polar nature of the acylguani-
dine moiety may have affected their permeability properties. As a
O
R2'
O
O
Br
4
R2'
O
R4
R4
5
a
3
NH2
NO2
NO2
OMe
7
N
N
N
6
H2N
NH2
H2N
b
b
OMe
N
R4
8
R4
N
8
N
R2'
R2'
11
R
4 = OMe
Route
c
e, f
g, h, f
X = O
a
b
9 (R4 = OH)
d
X = NH
NH2
NH2
X
OH
N
N
R4
RO
N
N
R2'
R2'
10
12; X = NH
13; X = O
Scheme 1. Reagents: (a) ZnCl2, Et3N, t-BuOH; (b) p-TsOH, toluene, EtOH; (c) BBr3, CH2Cl2; (d) RI, Cs2CO3, actetone; (e) ethanolamine, water, EtOH; (f) Fe, NH4Cl, MeOH, water;
(g) LiCl, DMF; (h) BrCH2CH2OH, K2CO3, DMSO.

2070
M. S. Malamas et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2068–2073
NH2
O
X
OH
OH
N
Br
O
O
N
N
21
N
a
Cl
O
N
N
N
Similar to Scheme 1
F
O
R2'
N
19
20
22; X = O
23: X = NH
O
O
b, c
RHN
O
R2'
R-NH2
HO
O
R2'
O
25
24
O
NH2
NH2
N
RHN
N
d
H2N
N
O
R2'
26
Scheme 3. Reagents: (a) K2CO3, DMAC; (b) SOCl2; (c) Et3N, THF; (d) p-TsOH, toluene, EtOH.
result the acylguanidines have demonstrated poor blood–brain
barrier permeability (<5%) in addition to weak inhibition in an ELI-
SA cell-based assay (EC50 >1 lM). As mentioned earlier, our objec-
tive was to identify a less polar bioisosteric replacement of the
acylguanidine moiety with improved physicochemical properties.
Toward this end, we have employed modeling and X-ray studies
and have discovered that the aminopyridine nucleus can success-
fully replace the acylguanidine moiety with comparable potency
(2 vs 1; Fig. 1). These new aminopyridine inhibitors, in general,
have reduced polar surface area (as measured by TPSA) relative
to the analogous acylguanidines (i.e., TPSA values 44 vs 86 for 2
vs 1). As expected, modulating this physicochemical parameter
has enhanced the brain permeability of compound 2, which
showed an excellent central drug exposure with a brain to plasma
ratio of 1.7, compared to 0.04 of compound 1. Having accomplished
our initial objective by effectively replacing the polar acylguani-
dine moiety with the aminopyridine group, next, we focused the
SAR studies on further improving the potency of this new class
of compounds. As can be seen, the docking of ligand 2 to the X-
ray crystal structure of the acylguanidine 1 bound to BACE1
(Fig. 2) has generated a nearly perfect superimposition of these
two ligands. The docking exercise further suggests that building
off the para-position of the phenyl moiety occupying the S1-pocket
would allow for projection directly towards the unoccupied S3 re-
gion. Following a similar SAR approach as we have disclosed with
the acylguanidines,14 we were able to improve the potency of tar-
get compound 2. To that end, introduction of alkoxy groups (Ta-
ble 1, entries 28–32) at the para-position of the P1 phenyl
Figure 2. Crystal structure of BACE1 complexed with 1 (shown in magenta) and 2
(shown in green) are overlayed. Key hydrogen-bonding interactions between ligand
1 and the protein’s catalytic aspartic acids Asp32 and Asp228 are highlighted with
blue dashed lines. Aminopyridine 2 superimposes almost perfectly with acylgua-
nidine 1.
NH2
NH2
NH2
N
resulted in an approximate 10-fold potency increase (30, 32 vs
2). While the five-carbon chain analogs 30 produced the most ac-
tive compound, both the shorter chained (entries 28–29) and long-
er chained-analogs (entry 31) were less potent. The three-carbon
nitrile analog 32 was similar to 30 in potency. As shown below
in the X-ray structure of 32 complexed with BACE1, the nitrile
group of 32 extends deep into S3 pocket, thus contributing to the
ligand affinity. Introduction of linear chain amides (entries 33–
36) at the para-position of the P1 phenyl have produced variable
results. Allyl-amide 36 was 10-fold better than 2, while the satu-
NH2
N
N
N
O
O
N
1
N
Cyclize
2
BACE1: IC50 3.7 uM
TPSA = 86.4
BACE1: IC50 5.2 uM
TPSA = 43.8
Figure 1. Bioisosteric replacement of the acylguanidine moiety.

M. S. Malamas et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2068–2073
2071
Table 1
Pyrrolyl 2-aminopyridines
NH2
N
R1
N
R2
Compd
R1
R2
BACE1 IC50
lM
BACE2 % Inh. 12.5
l
M
Cathepsin D % Inh. 12.5
lM
ELISA EC50 lM
2
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
H
OMe
O(CH2)2CH3
O(CH2)3CH3
O(CH2)4CH3
O(CH2)5CH3
O(CH2)3CN
C(@O)NHCH2CH3
C(@O)NH(CH2)2CH3
C(@O)NH(CH2)3CH3
C(@O)NH-allyl
C(@O)NH–CH(CH3)2
C(@O)NH-cyclopropane
C(@O)NH-cyclobutane
O-Ph
O-4-Pyridyl
O-3-Pyridyl
O-2-Pyridyl
O-5-Pyrimidinyl
O-2-Pyrazinyl
O-2-Pyridazinyl
O-2-Thiazole
NH-5-Pyrimidinyl
H
5.2 1.4a
2.45
1.15
15
30
48
31
31
13
IC50 = 7.1
36
28
5
12
7
6
6
0
26
9
15.4 0.9a
16 1.7
IA
IA
2.1 0.4
IA
5.2 0.9
IA
IA
nt
4.8 1.5
IA
IA
IA
9.2 1.5
4.8 1.2
IA
2-Cl
2-Cl
2-Cl
2-Cl
2-Cl
2-Cl
H
H
H
H
H
1.65
0.55 0.1
45% @ 12.5
0.42
2.25
3.0
3.0
0.59
1.78
1.2
3.4
0.85 0.2
0.59
0.41 0.2
0.81
0.1 0.02
0.46
0.41
0.29
0.98
lM
lM
IC50 = 44 .3
0
IC50 = 43.6
l
M
45
6.2
l
M
6.58
10.6
38.4
16
7.22
7.1 0.07
6.61
9.7 0.8
46.6
10.4
3.4
0
H
H
13
42.1
0
2-Cl
2-Cl
2-Cl
2-Cl
2-Cl
2-Cl
2-Cl
2-Cl
2-Cl
6
27
16
16
3
4
0
IA
2.2 0.5
13.3 1.2
IA
11.8 0.2
8.6 1.7
9.8
32
a
IC50 and EC50 values are the means of at least two experiments SD. Values without SD are for a single determination only.
rated alkyl amides (33–35) were only marginally improved. The
bulkier isopropyl- (37) and cycloalkyl-amides 38 and 39 were also
slightly better than 2.
Furthermore, to better fill the S3 region of the pocket, we have
explored aromatic groups (40–48) linked at the para-position of
the P1 phenyl with either an oxygen or a nitrogen atom. Despite
the increased substituent size, most aromatic analogs were about
5–10-fold more potent than the parent compound 2, with the nota-
ble example being the pyrimidinyl analog 44 which was the most
potent compound with an IC50 value of 100 nM for BACE1. Simi-
larly to the parent compound 2, aminopyridine 44 also demon-
strated high brain permeability with a brain to plasma ratio of
1.1, despite an increase of the compound’s total polar surface area
(TPSA = 79).
To further validate our modeling calculations, 44 was then co-
crystallized with the BACE1 enzyme, and as shown in Figure 3,
Figure 3. Crystal structure of BACE1 complexed with 44. Key hydrogen-bonding interactions between ligand and protein at the catalytic aspartic acids Asp32 and Asp228,
and the S3 conserved water are highlighted with blue dashed lines.

2072
M. S. Malamas et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2068–2073
Concomitant with these investigations, we explored analogs
that would be able to access the S10 region and potentially im-
prove potency further. Taking into account the findings of the
acylguanidine’s series14 and using molecular modeling tech-
niques, we have identified the potential of adding substituents
at position-3 of the aminopyridine moiety to extend deep into
the S10 region and improve ligand affinity. Additionally, the S10
region differs in size and relative hydrophobicity compared to
other aspartyl proteases, and thus affords an opportunity to im-
prove the ligand selectivity. Based on precedents from our previ-
ous SAR work with the acylguanidines,14,16,17 we have
introduced alkyl-hydroxyl groups at position-3 of the aminopyr-
idine moiety (Table 2, entries 49–54), which resulted in
enhancement of ligand potency. The oxo-ethyl-hydroxyl analog
49 was about 10-fold more potent than the lengthier propyl-hy-
droxyl analog 50. In contrast to this finding, the analogous ami-
no-alcohols 51 and 52 showed similar potency. Next, we
introduced the ethyl-hydroxyl group to the previously optimized
pyrimidinyl analog 44, and this combination has resulted in the
most potent compounds of this series. Analogs 53 and 54 exhib-
ited IC50 values of 40 and 70 nM, respectively, for BACE1. To our
satisfaction, their cell-based activity also tracked well with their
increased molecular binding. Not surprising, the introduction of
the alkyl alcohols have resulted in an increase of the TPSA value
of the molecule (TPSA >90) with the expected decrease in overall
brain permeability (brain to plasma ratio ꢀ0.25). Efforts to fur-
ther improve the potency of this class of BACE1 inhibitors with-
out affecting the molecular polarity (TPSA, etc.) and brain
permeability will be the subject of a later disclosure.
The aminopyridine inhibitors were also evaluated against
BACE2 and cathepsin D. The BACE2 selectivity ranged between
10–130-fold, while they were even more selective against cathep-
sin D (>100-fold), with the most potent inhibitor 53 (IC50 = 40 nM)
showing >100-fold selectivity against BACE2, and >500-fold
against cathepsin D.
In summary, we have described the discovery of the 2-amino-
pyridine moiety as a bioisosteric replacement of the acylguanidine
moiety with lower TPSA values and superior brain penetration.
Several analogs have shown low nanomolar potency and >100-fold
selectivity against BACE2 and cathepsin D. X-ray crystallographic
studies indicated that the 2-aminopyridine moiety interacts di-
rectly with the catalytic aspartic acids Asp32 and Asp228 via a
hydrogen-bonding network. Key substitutions at the P1 phenyl
and the aminopyridine moiety of the ligand, extend deep into S3
and S10 regions enhancing the ligand’s affinity.
Figure 4. Crystal structures of BACE1 complexed with 32 (magenta) and 44 (shown
in green) are overlayed. Substituents at the para-position of the P1 phenyl project
deep into S3 pocket. The aminopyridine moiety orients toward the catalytic region
of the enzyme and the pyrrole ring of the ligand points toward the FLAP region,
making a p-edge stacking interaction with Tyr71.
the pyrimidine moiety projects deep into S3 pocket and makes a
water-bridge contact with Ser229 through the buried conserved
water found near the catalytic site of the enzyme. This water-
bridge contact together with the additional van der Walls contacts
between the ligand and enzyme backbone at the S3 region are con-
sistent with the ligand’s increased potency. In addition, the crystal
structure shows that both the amino group and the pyridine nitro-
gen of the aminopyridine moiety make direct contacts with the
catalytic aspartic acids Asp32 and Asp228 via a hydrogen-bonding
network as expected. Finally the P1 and P20 phenyls make van der
Waals interactions at the S1 and S20 pockets, while the pyrrole ring
of the ligand points toward the FLAP region, presumably making a
p-edge stacking interaction with Tyr71.
In order to confirm the orientation of the alkyl chain of the li-
gands that bear such a group at the para-position of the P1 phenyl,
analog 32 was also co-crystallized with BACE1. The examination of
the BACE1:32 structure overlayed with 44 (Fig. 4) revealed both
molecules superimpose very well and the alkyl chain of 32 orients
similar to the aromatic group of 44, extending deep into the S3
pocket.
Table 2
Substituted aminopyridines
NH2
R3
N
R1
N
Cl
Compd
R1
R3
BACE1 IC50
0.11a
lM
BACE2 % Inh. 12.5
lM
Cathepsin D % Inh. 12.5
lM
ELISA EC50 lM
13.6 2.1a
IA
3.2 0.8
IA
0.44 0.04
0.19 0.04
49
50
51
52
53
54
O(CH2)4CH3
O(CH2)4CH3
O(CH2)4CH3
O(CH2)4CH3
O-5-Pyrimidinyl
O-5-Pyrimidinyl
O(CH2)2OH
O(CH2)3OH
NH(CH2)2OH
NH(CH2)3OH
O(CH2)2OH
NH(CH2)2OH
1.7
47
IC50 = 1.0
IC50 = 0.47
5.43
4
0
43
46% @ 1
0.17
l
M
0.22
0.04 0.01
0.07
IC50 = 7.2 0.9
23
31
8.46
a
IC50 and EC50 values are the means of at least two experiments SD. Values without SD are for a single determination only.

M. S. Malamas et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2068–2073
2073
12. Alloul, K.; Sauriol, L.; Kennedy, W.; Laurier, C.; Tessier, G.; Novosel, S.;
Contandriopoulos, A. Arch. Gerontol. Geratr. 1998, 27, 189.
References and notes
13. (a) Enz, A.; Amstutz, R.; Boddeke, H.; Gmelin, G.; Malanowski, J. Prog. Brain Res.
1993, 98, 431; (b) Fillit, H.; Hill, J. Am. J. Geriatr. Pharmacother. 2005, 3, 39.
14. Cole, D. C.; Manas, E. S.; Stock, J. R.; Condon, J. S.; Jennings, L. D.; Aulabaugh, A.;
Chopra, R.; Cowling, R.; Ellingboe, J. W.; Fan, K. Y.; Harrison, B. L.; Hu, Y.;
Jacobsen, S.; Jin, G.; Lin, L.; Lovering, F. E.; Malamas, M. S.; Stahl, J.; Strand, J.;
Sukhedo, M. N.; Svenson, K.; Turner, M. J.; Wagner, E.; Wu, J.; Zhou, P.; Bard, J. J.
Med. Chem. 2006, 49, 6158.
15. Stachel, S.; Coburn, C.; Rush, D.; Jones, K.; Zhu, H.; Rajapakse, H.; Graham, S. L.;
Simon, A.; Holloway, M. K.; Allison, T. J.; Munshi, S. K.; Espeseth, A. S.; Zuck, P.;
Colussi, D.; Wolfe, A.; Pietrak, B. L.; Lai, M.; Vacca, J. Bioorg. Med. Chem. Lett.
2009, 19, 2977.
16. Cole, D.; Stock, J.; Chopra, R.; Cowling, R.; Ellingboe, J.; Fan, K.; Harrison, B.; Hu,
Y.; Jacobsen, S.; Jennings, L.; Jin, G.; Lohse, P.; Malamas, M. S.; Manas, E.; Moore,
W.; O’Donnell, M.; Olland, A.; Robichaud, A.; Svenson, K.; Wu, J.; Wagner, E.;
Bard, J. Bioorg. Med. Chem. Lett. 2008, 18, 1063.
17. Jennings, L.; Cole, D.; Stock, J.; Sukhdeo, M.; Ellingboe, J.; Cowling, R.; Jin, G.;
Manas, E.; Fan, K.; Malamas, M. S.; Harrison, B.; Jacobsen, S.; Chopra, R.; Lohse,
P.; Moore, W.; O’Donnell, M.; Hu, Y.; Robichaud, A.; Turner, J.; Wagner, E.;
Jonathan Bard Bioorg. Med. Chem. Lett. 2008, 18, 767.
1. Enz, A.; Amstutz, R.; Boddeke, H.; Gmelin, G.; Malanowski, J. Am. J. Geriatr.
Pharmacother. 2005, 3, 39.
2. Arendt, T. Neuroscience 2001, 102, 723.
3. Dickson, D. W. J. Neuropathol. Exp. Neurol. 1997, 56, 321.
4. (a) Selkoe, D. J. Science 1997, 275, 630; (b) Hardy, J.; Selkoe, D. J. Science 2002,
297, 353.
5. Vassar, R.; Citron, M. Neuron 2000, 27, 416.
6. Selkoe, D. J. Physiol. Rev. 2001, 81, 741.
7. Hussain, I.; Powell, D.; Howlett, D. R.; Tew, T. G.; Meek, T. D.; Chapman, C.;
Gloger, I. S.; Murphy, K. E.; Southan, C. D.; Ryan, D. M.; Smith, T. S.; Simmons, D.
L.; Walsh, F. S.; Dingwall, C.; Christie, G. Mol. Cell Neurosci. 1999, 14, 419.
8. Lin, X.; Koelsch, G.; Wu, S.; Downs, D.; Dashti, A.; Tang, J. Proc. Natl. Acad. Sci.
U.S.A. 2000, 97, 1456.
9. Sinsa, S.; Anderson, J. P.; Barbour, R.; Basi, G. S.; Caccavello, R.; Davis, D.; Doan,
M.; Dovey, H. F.; Frigon, N.; Hong, J.; Jacobson-Croak, K.; Jewett, N.; Keim, P.;
Knops, J.; Lieberburg, I.; Power, M.; Tan, H.; Tatsuno, J.; Tung, J.; Schenk, D.;
Seubert, P.; Suomensaari, S. M.; Wang, S.; Walker, D.; Zhao, J.; McColongue, L.;
John, V. Nature 1999, 402, 537.
10. Vassar, R.; Bennett, B. D.; Babu-Khan, S.; Kahn, S.; Mendiaz, E. A.; Denis, P.;
Teplow, D. B.; Ross, S.; Amarante, P.; Loeloff, R.; Luo, Y.; Fischer, S.; Fuller, J.;
Edenson, S.; Lile, J.; Jarosinski, M. A.; Biere, A. L.; Curran, E.; Burgess, T.; Louis, J.-
C.; Collins, F.; Treanor, J.; Rogers, G.; Citron, M. Science 1999, 286, 735.
11. Selkoe, D. J. Ann. Intern. Med. 2004, 140, 627.
18. Nevar, N. M.; Kelin, A. V.; Kulinkovich, O. G. Synthesis 2000, 1259.
19. Detailed experimental of the preparation of the compounds described in this
Letter are reported in US Patent 0173049, 2006.