Synthesis and SAR of hydroxyethylamine based phenylcarboxyamides as inhibitors of BACE

Article abstract of DOI:10.1016/j.bmcl.2009.03.144

A series of N-((2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-(3-methoxybenzylamino)-butan-2-yl)benzamides has been synthesized as BACE inhibitors. A variety of P2 and P3 substituents has been explored, and these efforts have culminated in the identification

Full text of DOI:10.1016/j.bmcl.2009.03.144

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2654–2660
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and SAR of hydroxyethylamine based phenylcarboxyamides
as inhibitors of BACE
a
b
c
c
Yong-Jin Wu a, , Yunhui Zhang , Andrew C. Good , Catherine R. Burton , Jeremy H. Toyn ,
*
Charles F. Albright c, John E. Macor a, Lorin A. Thompson a
a Neuroscience Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA
b Computer-Aided Drug Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA
c Neuroscience Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of N-((2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-(3-methoxybenzylamino)-butan-2-yl)benz-
amides has been synthesized as BACE inhibitors. A variety of P2 and P3 substituents has been explored,
and these efforts have culminated in the identification of several 1,3,5-trisubstituted phenylcarboxya-
mides with potent BACE inhibitory activity.
Received 2 March 2009
Revised 25 March 2009
Accepted 30 March 2009
Available online 5 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
BACE inhibitor
Phenylcarboxyamides
Alzheimer’s disease
Diverse lines of evidence suggest that b-amyloid (Ab) peptide,
particularly the longer 42 amino acid form, Ab42, plays a critical
role in the progression of Alzheimer’s disease (AD).1–3 Although
Ab is a major constituent of the neuritic plaques that are charac-
teristic of the AD brain, recent studies suggest that soluble forms
of Ab, potentially including oligomeric, protofibrillar, and intra-
cellular Ab, may play a dominant role in the disease process.4–8
Ab is derived from the b-amyloid precursor protein (APP) by pro-
teolysis. Cleavage of APP by b-site APP cleaving enzyme (BACE)
results in the shedding of the APP ectodomain, and the remaining
membrane bound C-terminal fragment, C99, is further processed
BACE is a type I membrane-associated aspartyl protease. The
commonly utilized fragments that interact with the catalytic
aspartates are transition state isosteres including the hydroxy-
ethylamine dipeptide isosteres (HEA). In fact, the HEA fragment
has been incorporated as part of the central core into a number
of BACE inhibitors as exemplified by isophthalamide 1a (Fig. 1),
which was previously disclosed by Maillard et al.12 This com-
pound exhibited good enzyme (IC50 = 20 nM) and cellular activ-
ity (IC50 = 15 nM). In our own work, we have focused on HEA
isostere-based inhibitors with substituted lactams as P2–P3
headgroups,13 and we have noted increases in binding potency
with appropriately placed P2 substituents. Compound 1a
seemed to offer a unique and possibly smaller molecular weight
scaffold as a P2–P3 linking group, but with the P2 region of the
inhibitor mostly unexplored. Examination of the published X-ray
structure of the 3-iodophenyl analog 1b12 suggested a hydrogen
bonding network was formed between a heteroatom of the C-3
substituent, residues in the P3 pocket, and an interstitial water
molecule at the P2/P3 interface (see Fig. 2b, vide infra). In an at-
tempt to improve the affinity in this series further, we intro-
duced a series of C-3 substituents of the isophthalate bearing a
heteroatom such as the carbonyl oxygen in an acetyl group in
an attempt to both gain affinity in the P2 pocket and displace
the water molecule with a substituent on the inhibitor. This Let-
ter describes the synthesis and SAR of the resulting 3-substi-
tuted hydroxyethylamine based phenylcarboxyamides as
inhibitors of BACE.
by
(AICD), respectively.9 BACE and
tive pharmaceutical targets because of their roles in Ab genera-
tion. However, -secretase also cleaves other transmembrane
proteins, including Notch, which is involved in cell differentiation.
Thus, chronic high doses of -secretase inhibitors may disrupt
c
-secretase to produce Ab and the APP intracellular domain
c-secretase are therefore attrac-
c
c
Notch-mediated processes in the gastrointestinal tract, spleen,
and thymus leading to potential mechanism-based toxicity. In
contrast, Notch inhibition is not expected for BACE inhibitors,
potentially making BACE a more attractive therapeutic target for
AD.10,11
* Corresponding author. Tel.: +1 203 677 7485; fax: +1 203 677 7702.
E-mail address: yong-jin.wu@bms.com (Y.-J. Wu).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.144

Y.-J. Wu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2654–2660
2655
Me
OH Boc
N
CBz
O
H2N
HN
OH
d-e
a-c
OMe
H
N
H
N
N
F
F
R
O
O
F
1b (R = I)
1a (R = OMe)
IC50 = 20 nM (binding)
IC50 = 15 nM (cellular)
8
9
F
F
F
OH
H
N
H
N
Ar
Figure 1.
OMe
O
F
Phenylcarboxyamides 1–7 for this study are shown in Tables
1–4. These compounds were prepared according to Scheme 1.
The key primary amine intermediate 9 was obtained from the
known epoxide 812,14 in three steps: lithium perchloride-in-
duced epoxide opening with (3-methoxyphenyl)methanamine;
F
1-7
Scheme 1. Reagents and conditions: (a) (3-methoxyphenyl)methanamine, LiClO4,
MeCN, 60 °C, 65%; (b) Boc2O, Et3N, CH2Cl2 78%; (c) 10% Pd/C, EtOH, H2 (50 psi), 95%;
(d) ArCO2H, HATU, Et3N, DMF, 60–95%; (e) TFA, CH2Cl2, 90–100%.
Figure 2. (a) (Left) Model of compound 1c in human BACE-1. (b) (Right) Docked inhibitor 1d in BACE-1 enzyme. Hydrophobic interaction with S3 pocket (light blue circle); H-
bonds through interstitial water and N233/T232 (red arrow); H-bond to backbone of T232 (deep yellow arrow); metastable interaction to Q73 (pink circle); H-bond of the
acetyl oxygen to interstitial H2O (deep blue arrow); hydrophobic interaction of the acetyl methyl with T72 side chain (yellow circle).
Table 1
Binding and Cellular IC50 values of 3-substituted isophthalamides
R
OH
H
N
H
N
N
OMe
O
O
F
1
F
O
HO
Me
MeO
Me
allylO
Me
i-BuO
Me
BnO
Me
OH
OH
OMe
NH2
NHAc
OH
N
N
N
N
N
MeO
R
H
Me
Me
Me
Me
Me
Compd
1c 1d
1e
3
27
1f
1
42
1g
10
120
1h
55
367
1i
67
534
1j
2
12
1k
16
34
1m
10
53
1n
>2000
NA
1p
123
640
1q
20
45
IC50 (nM)a,c 31
4
IC50 (nM)b,c 80 19
a
Binding data.
Cellular data.
Average of 2–4 determinations.
b
c

2656
Y.-J. Wu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2654–2660
O
Me
21
protection of the secondary amine; and selective deprotection of
the Cbz group to give primary amine 9. Coupling of amine 9
with various arylcarboxylic acids using HATU and subsequent
deprotection of the Boc group provided amides 1–7.
Br
Br
a
b-c
O
O
O
O
S
CO2Me
I
CO2Me
Br
S
CO2Me
Me
O
17
Me
18
The arylcarboxylic acids required for the synthesis of amides
1–7 were generally derived from the corresponding methyl ben-
zoates. Scheme 2 describes the preparation of the 3-substituted
methyl 5-(di-alkylcarbamoyl)benzoate 16 from the commercially
available 3-(methoxycarbonyl)-5-nitrobenzoic acid (10). Catalytic
hydrogenation of 10 followed by Sandmeyer reaction gave bro-
mide 11, which was coupled with various amines to provide
bromophenylcarboxyamides 12. These bromides underwent the
palladium-catalyzed Heck vinylation reactions under microwave
irradiation, and the resulting aryl vinyl ethers were hydrolyzed
in situ with hydrochloric acid to give the methyl ketones 13.15
Reduction of the ketone moiety with sodium borohydride fur-
nished alcohols 14, which were converted to azides 15 using di-
phenyl phosphorazidate (DPPA). Oximation of 13 proceeded
smoothly to give a mixture of two oxime isomers 16. The methyl
3-(1-azidoethyl)-5-(di-propylcarbamoyl)benzoate 15 was con-
verted to the final 3-(1-aminoethyl)-phenylcarboxyamide 1 m
(Table 1) in a 4 step sequence: hydrolysis of the methyl ester,
coupling with amine 9; catalytic hydrogenation of azide to amine
(10% Pd/C, EtOAc, hydrogen balloon); and deprotection of the Boc
group.
e
d
Br
O
O
O
S
S
N
CO2Me
Me
N
CO2Me
R
20
19
b-c
b-c
O
Me
O
Me
O
O
O
O
S
S
N
CO2Me
Me
N
R
CO2Me
22
23
Scheme 3. Reagents and conditions: (a) (CuOTf)2ꢀPhH (5 mol %), N,N0-dimethyleth-
ylenediamine (10 mol %), MeS(O)ONa, toluene, 90 °C, 65%; (b) 1-(vinyloxy)butane,
Pd(OAc)2, DPPP, K2CO3, DMF, H2O; (c) HCl, 35% over two steps; (d) Pd2(dba)3,
xantphos, Cs2CO3, RNHSO2Me, toluene, 90 °C, 56%; (e) Pd2(dba)3, xantphos, Cs2CO3,
1,4-butanesultam, toluene, 90 °C, 57%.
Scheme 3 describes the preparation of 3-acetyl-5-(sulfon-
amido)benzoates required for the synthesis of amides 4–6
shown in Table 3. The copper-catalyzed coupling of methyl
(Table 4). The copper-catalyzed arylation of phenols and arylthiols
with bromide 12 under microwave irradiation generated aryl
ethers 24 and aryl sulfides 25, respectively.17 Oxidation of sulfide
25 with mCPBA led to sulfones 26.
Primary inhibitor potency was measured in a standard radioli-
gand displacement assay with the radiolabelled BACE inhibitor
[3H]BMS-599240.18 The cell-based assay was used to measure
the amount of inhibition of Ab40 production by native BACE-1 en-
zyme in HEK cells overexpressing APP with the Swedish
mutation.19
The binding and cellular IC50 values of the 3-substituted isoph-
thalamides are shown in Table 1. Among the oxime series, meth-
oxyoxime 1f, hydroxyoxime 1e and methylketone 1d were the
best in terms of both binding affinity and cellular activity (bind-
ing IC50 < 5 nM; cellular IC50 < 50 nM), and they were superior to
the unsubstituted compound 1c (binding IC50 = 31 nM; cellular
IC50 = 80 nM). In general, the inhibitory activity (both binding
and cellular) of the oxime analogs decreased as the alkyl group
of the oxime moiety becomes bulkier. The 3-(1-hydroxyethyl)
analog 1j also exhibited potent inhibitory activity in both assays.
NO2
Br
Br
a-b
Me
R1
N
c
HO2C
d-e
CO2Me
O
HO2C
CO2Me
R2
CO2Me
11
10
12
O
N
Me
R3O
f
R1
N
R1
N
R2
CO2Me
R2
CO2Me
O
O
13
16
g
HO
Me
N3
Me
h
R1
N
R1
N
R2
CO2Me
R2
CO2Me
In comparison with the
a-hydroxyl analog 1j, both b-hydroxyl
O
O
derivatives 1k and 1m were several-fold less potent in terms of
the binding affinity, but they still showed enhanced potency to-
ward BACE-1 relative to the unsubstituted compound 1c. The
15
14
Scheme 2. Reagents and conditions: (a) 10% Pd/C, H2, EtOH, 85%; (b) t-BuONO,
CuBr2, DMF, 55%; (c) R1R2NH, HATU, CH2Cl2, 75–95% (d) 1-(vinyloxy)butane,
Pd(OAc)2, DPPP, K2CO3, DMF, H2O; (e) HCl, 35–55%; (f) R3ONH2ꢀHCl, EtOH, 80 °C,
85%; (g) NaBH4, EtOH, 94%; (h) (PhO)2PON3, Hünig’s base, toluene, 78%.
X
Ar
Br
a
b
N
N
X = S
3-bromo-5-iodobenzoate (17) with sodium methanesulfinate
provided methylsulfone 18, and the palladium-catalyzed reac-
tion of 17 with the N-substituted methanesulfonamide and
1,4-butanesultam furnished sulfonamide 19 and sultam 20,
respectively.16 The introduction of the acetyl group onto 18,
19 and 20 was carried out in the same fashion as 12 to 13
(Scheme 2) to give the corresponding ketone esters 21, 22
and 23.
CO2Me
CO2Me
O
O
12
24 (X = O)
25 (X = S)
O
Ar
S
O
N
CO2Me
O
26
Scheme 4 describes the synthesis of methyl 3-(di-propylcarba-
moyl)-5-phenoxy, 5-phenylthio, and 5-phenylsulfonyl benzoates
that were used for the synthesis of compounds with formula 7
Scheme 4. Reagents and conditions: (a) ArOH or ArSH, CuI, Cs2CO3, NMP, 195 °C,
35%; (b) mCPBA, CH2Cl2, 65%.

Y.-J. Wu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2654–2660
2657
Table 2
IC50 values of (1-phenylethyl)isophthalamides
R
R
F
OH
OH
H
N
H
N
H
N
H
N
H
H
N
N
OMe
OMe
Me
O
O
F
Me
O
O
F
3
2
F
F
O
OH
MeO
Me
Oallyl
Me
O
OH
MeO
Me
Oallyl
Me
N
N
N
N
R
H
H
Me
Me
Me
Me
Compd
2a
89
198
2b
20
73
2c
29
92
2d
32
82
2e
86
500
3a
166
266
3b
51
91
3c
37
164
3d
24
276
3e
168
530
IC50 (nM)a,c
IC50 (nM)b,c
a
Binding data.
Cellular data.
Average of 2–4 determinations.
b
c
bis-methoxy analog 1n was devoid of measurable inhibitory
activity. Replacement of the hydroxyl in 1j with primary amine
(see 1p) dramatically reduced inhibitory activity, but the activity
was partially restored through acetylation of the primary amine
in 1p (see 1q). The same set of substituents was also introduced
onto the N-methyl-N-propylisophthalamide series, and the SAR
was similar to that observed in the N,N-diisopropylisophthala-
mide series (data not shown).
In the isophthalamide series, the 3-acetyl group enhanced
binding activity by up to eightfold. This enhancement can be
rationalized by examining the binding model of compound 1d
in comparison with a model of the unsubstituted compound
1c. All compounds were modeled starting from the reported
crystal structure12 of the 3-iodophenyl analog 1b using Maestro
7.5.1 (Schrodinger Inc, 120 West 45th Street, 29th floor New
York NY 10036.) According to this model, the acetyl group is en-
gaged in a hydrogen bonding interaction with the interstitial
water in the S2 pocket, leading to the observed modest increase
Recently, Stachel et al. demonstrated that the N,N-diisopropyl
group of the isophthalamide series can be effectively replaced
with
a
-methylbenzyl amine moiety.20,21 To this end, we sought
in enzyme affinity. Like the acetyl group, the oxime and
hydroxylethyl groups are expected to create similar hydrogen
bonding networks. The -aminoethyl at C-3 of 1p (Table 1)
a-
to determine the impact of the 3-substituents onto the
a
-meth-
ylbenzamide class of inhibitors. The IC50 values of these analogs
are summarized in Table 2. Again, acetyl (2b and 3b), 1-hydroxy-
ethyl (2c and 3c) and 1-(methoxyimino)ethyl (3d) enhanced
inhibitory activity by 2–4-fold in both assays. The O-allyl oxime
analogs 2e and 3e were comparable to their respective unsubsti-
tuted compound 2a and 3a.
a
should be protonated under physiological conditions and is unli-
kely to participate in hydrogen bonding to the interstitial water,
and it also generates electrostatic repulsion with R235. In con-
trast, the
interaction with the enzyme through the interstitial water. As
a result, the -aminoethyl moiety of 1p (Table 1) reduced bind-
a-acetamidoethyl group of 1q can take part in the
A series of 3-substituted sulfonamides 4–6 was also prepared,
and the IC50 values of these compounds are summarized in Table
a
ing activity of isophthalamides, while the
a-acetamidoethyl in
3. The impact of the 3-substituents such as acetyl and
a
-hydroxy-
1q maintained good activity.
ethyl was less pronounced than that observed in the isophthalamide
series. For example, the acetyl analogs 4b, 5b and 6b were slightly
less active than their respective unsubstituted compounds 4a, 5a
and6a inthebindingassay, as opposedto2–8-foldenhancementob-
served in the isophthalamide series. Of particular interest is that the
benzyloxime analogs 4i, 5i and 6i were significantly more active
than their respective iso-butyloxime counterparts 4h, 5h and 6h in
the binding assay. In contrast, both benzyloxime (1g) and iso-buty-
loxime (1f) of the isophthalamide series (Table 1) exhibited similar
inhibitory activity. Thus, this benzyl effect improving potency ap-
peared to be unique to the sulfonamide series.
The impact of the C-3 acetyl and the a-hydroxyethyl, as well as
the benzyloxime in the sulfonamide series (Table 3) differed from
the trend observed in the isophthalamide series (Table 1) because
they occupy different spaces in the active site. In the isophthala-
mide series, the acetyl group is located within the S2 pocket, while
the diisopropyl moiety occupies the S3 pocket. However, in the sul-
fonamide series, the phenyl group rotates, placing the acetyl group
in the S3 pocket, and the methylsulfonamido group in the S2 pock-
et. The sulfonamide of isophthalamides is known to occupy the S2
site.22 Figure 3a displays a binding model for inhibitor 2719 in the
BACE-1 active site based on its x-ray structure,20 and Figure 3b
shows a binding model of the E-isomer of sulfonamide 4i. The sul-
fonamide moiety of both inhibitors fills the S2 pocket, and the
hydrophobic interaction of the phenyl with the S3 pocket is also
similar. Both compounds appear to bind with BACE1 enzyme in
the same fashion, thereby resulting in comparable intrinsic inhib-
itory activity.
In addition to the acetyl, a-hydroxylethyl and oximes, we also
investigated the impact of phenyloxy, phenylthio and phenylsul-
fonyl in the isophthalamide series as shown in Table 4. In gen-
eral, these analogs showed slightly enhanced binding affinity
with the exception of 7c, but their cellular activity was signifi-
cantly diminished, presumably due to the increased molecular
weight and size.

2658
Y.-J. Wu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2654–2660
Table 3
IC50 values of sulfonamides
R
OH
H
N
H
N
Me
N
Ph
N
4
5
6
Y
OMe
N
Me
Me
O
F
Y =
Y =
Y =
S
S
S
O
O
O
O
O
O
F
O
OH
HO
Me
MeO
n-PrO
Me
allyl-O
Me
i-BuO
Me
BnO
Me
N
N
N
N
N
N
R
H
Me
Me
Me
Compd
4a
74
182
5a
75
80
6a
11
137
4b
90
4c
43
305
5c
43
122
6c
NA
NA
4d
38
117
5d
76
429
6d
9
4e
4f
4g
4h
4i
IC50 (nM)a,c
IC50 (nM)b,c
Compd
52
345
5e
60
52
6e
10
86
25
205
5f
59
217
6f
111
1232
5g
151
363
6g
428
2098
5h
173
>666
6h
31
821
5i
9
>333
6i
248
5b
124
559
6b
IC50 (nM)a,c
IC50 (nM)b,c
Compd
IC50 (nM)a,c
IC50 (nM)b,c
17
>263
6
184
27
162
242
NA
12
88
91
a
Binding data.
Cellular data.
Average of 2–4 determinations.
b
c
Table 4
IC50 values of sulfonamides
R
OH
H
H
N
N
N
OMe
O
O
F
7
F
OMe
O
F
OMe
OMe
OMe
O
O
O
S
S
R
H
O
O
O
S
S
O
Compd
1a
31
80
7a
10
>333
7b
10
412
7c
54
>666
7d
22
94
7e
13
>333
7f
27
30
7g
11
148
7h
12
392
IC50 (nM)a,c
IC50 (nM)b,c
a
Binding data.
Cellular data.
Average of 2–4 determinations.
b
c

Y.-J. Wu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2654–2660
2659
Figure 3. (a) (Left). Binding model of inhibitor 27 (Merck)19 based on its X-ray crystal structure with human BACE-1. (b) (Right) Docked inhibitor 5i (E-isomer) in BACE-1
enzyme. hydrophobic interaction with S3 pocket (light blue circle); H-bonds to SO2 displacing interstitial H2O (red); H-bond to backbone of G230 (yellow) (only in 27);
hydrophobic interaction with T72 side chain (light green circle).
Me
O
O
Me
S
S
S3
S2
HO
S2
N
N
O
O
S3
OH
Ph
5pc
H
N
H
N
H
N
H
N
NH
N
O
OMe
Me
O
O
Me
O
Ph-3,5-di-F
27
4i
6. Wilson, C. A.; Doms, R. W.; Lee, V. M. J. Neurosci. Res. 2003, 74, 761.
7. Shankar, G. M.; Li, S.; Mehta, T. H.; Garcia-Munoz, A.; Shepardson, N. E.; Smith,
I.; Brett, F. M.; Farrell, M. A.; Rowan, M. J.; Lemere, C. A.; Regan, C. M.; Walsh, D.
M.; Sabatini, B. L.; Selkoe, D. J. Nat. Medicine 2008, 14, 837–842.
8. Klyubin, I.; Betts, V.; Welzel, A. T.; Blennow, K.; Zetterberg, H.; Wallin, A.;
Lemere, C. A.; Cullen, W. K.; Peng, Y.; Wisniewski, T.; Selkoe, D. J.; Anwyl, R.;
Walsh, D. M.; Rowan, M. J. J. Neurosci. 2008, 28, 4231.
9. Lundkvist, J.; Naslund, J. Curr. Opin. Pharmacol. 2007, 7, 112.
10. John, V.; Beck, J. P.; Bienkowski, M. J.; Sinha; HeinriksonSinha, R. L. J. Med. Chem.
2003, 46, 4625.
The acetyl,
a-hydroxyethyl and a-methoxyiminoethyl at C-3 gen-
erally enhanced binding affinity in the isophthalamide series pre-
sumably due to the hydrogen bonding network created through
their positive interaction with interstitial water in the enzyme,
as well as hydrophobic interaction with T72 side chain. The isoph-
thalamides with acetyl or
a-hydroxyethyl groups at C-3 also
exhibited optimal cellular activity. However, these substituents
show less pronounced effects in the sulfonamide series because
they occupy the S3 pocket instead of the S2 pocket, as in the case
of isophthalamides. The structure-based optimization for potency
led to several 1,3,5-trisubstituted phenylcarboxyamides with po-
tent cellular activity (IC50s < 100 nM). However, these compounds
were shown to be Pgp substrates and had poor pharmacokinetic
properties.22,23 Our efforts to address both of these liabilities will
be reported in due course.
11. McConlogue, L.; Buttini, M.; Anderson, J. P.; Brigham, E. F.; Chen, K. S.;
Freedman, S. B.; Games, D.; Johnson-Wood, K.; Lee, M.; Zeller, M.; Liu, W.;
Motter, R.; Sinha, S. J. Biol. Chem. 2007, 282, 26326.
12. Maillard, M. C.; Hom, R. K.; Benson, T. E.; Moon, J. B.; Mamo, S.; Bienkowski, M.;
Thomasselli, A. G.; Woods, D. D.; Prince, D. B.; Paddock, D. J.; Emmons, T. L.;
Tucker, J. A.; Dappen, M. S.; Brogley, L.; Thorsett, E. D.; Jewett, N.; Sinha, S.;
Varghese, J. J. Med. Chem. 2007, 50, 776; For recent progress in this area, see:
Charrier, N.; Clarke, B.; Cutler, L.; Demont, E.; Dingwall, C.; Dunsdon, R.; East,
P.; Hawkins, J.; Howes, C.; Hussain, I.; Jeffrey, P.; Maile, G.; Matico, R.; Mosley,
J.; Naylor, A.; O’Brien, A.; Redshaw, S.; Rowland, S.; Soleil, V.; Smith, K. J.;
Sweitzer, S.; Theobald, P.; Vessey, D.; Walter, D. S.; Wayne, G. J. Med. Chem.
2008, 51, 3313; Rizzi, L.; Vaiana, N.; Sagui, F.; Genesio, E.; Pilli, E.; Porcari, V.;
Romeo, S. Protein Pept. Lett. 2009, 16, 86.
Acknowledgments
13. (a) Boy, K. M.; Guernon, J. M.; Shi, J.; Zheng, C.; Liauw, A.; Bronson, J. J.; Macor, J.
E.; Combs, A. P.; Trainor, G.; Decicco, C. P.; Good, A.; Tebben, A. J.; Toyn, J. H.;
Burton, C. R.; Barten, D. M.; Marcinkeviciene, J.; Copeland, R. A.; Muckelbauer, J.
K.; Morin, P. E.; Lentz, K.; Albright, C.; Thompson, L. A. Abstracts of Papers,
233rd ACS National Meeting, Chicago, IL, United States, March 25–29, 2007,
MEDI-235; (b) Thompson, L. A.; Boy, K. M.; Shi, J.; Macor, J. E. U.S. Pat. Appl.
Publ. 2006, US 2006046984 A1.
We thank Carol Krause, Cathy Kieras, Lynn Balanda, Barbara
Robertson and Larry Iben for carrying out biological assays.
14. Rotella, D. Tetrahedron Lett. 1995, 36, 5453.
References and notes
15. Vallin, K. S. A.; Larhed, M.; Hallberg, A. J. Org. Chem. 2001, 66, 4340.
16. Steinhuebel, D.; Palucki, M.; Askin, D.; Dolling, U. Tetrahedron Lett. 2004, 45,
3305.
17. Wu, Y. -J.; He, H. Synlett 2003, 1789.
18. Iben, L. G.; Kopcho, L.; Marcinkeviciene, J.; Zheng, C.; Thompson, L. A.; Albright,
C. F.; Toyn, J. H. Eur. J. Pharmacol. 2008, 593, 10–15.
1. For recent reviews, see: Barten, D. M.; Albright, C. F. Mol. Neurobiol. 2008, 37,
171; Marcello, E.; Epis, R.; Luca, M. D. Eur. J. Pharmacol. 2008, 585, 109; LaFerla,
F. M.; Green, K. N.; Oddo, S. Nat. Rev. Neurosci. 2007, 8, 499.
2. Hardy, J.; Selkoe, D. J. Science 2002, 297, 353–356.
19. Burton, C. R.; Meredith, J. E.; Barten, D. M.; Goldstein, M. E.; Krause, C. M.;
Kieras, C. J.; Sisk, L.; Iben, L. G.; Polson, C.; Thompson, M. W.; Lin, X.; Corsa, J.;
Fiedler, T.; Pierdomenico, M.; Cao, Y.; Roach, A. H.; Cantone, J. L.; Ford, M. J.;
Drexler, D. M.; Olson, R. E.; Yang, M. G.; Bergstrom, C. P.; McElhone, K. E.;
3. Selkoe, D. J. Neuron 1991, 6, 487.
4. Caughey, B.; Lansbury, P. T. Annu. Rev. Neurosci. 2003, 26, 267.
5. Cleary, J. P.; Walsh, D. M.; Hofineister, J. J.; Shankar, G. M.; Kuskowski, M. A.;
Selkoe, D. J.; Ashe, K. H. Nat. Neurosci. 2005, 8, 79.

2660
Y.-J. Wu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2654–2660
Bronson, J.; Macor, J. E.; Blat, Y.; Grafstrom, R. H.; Stern, A. M.; Seiffert, D. A.;
22. Stanton, M. G.; Stauffer, S. R.; Gregro, A. R.; Steinbeiser, M.; Nantermet, P.;
Sankaranarayanan, S.; Price, E. A.; Wu, G.; Crouthamel, M.; Ellis, J.; Lai, M.;
Espeseth, A. S.; Shi, X.; Jin, L.; Colussi, D.; Pietrak, B.; Huang, Q.; Xu, M.; Simon,
A. J.; Graham, S. L.; Vacca, J. P.; Selnick, H. J. Med. Chem. 2007, 50, 3431.
23. Meredith, J. E., Jr.; Thompson, L. A.; Toyn, J. H.; Marcin, L.; Barten, D. M.;
Marcinkeviciene, J.; Kopcho, L.; Kim, Y.; Lin, A.; Guss, V.; Burton, C.; Iben, L.;
Polson, C.; Cantone, J.; Ford, M.; Drexler, D.; Fiedler, T.; Lentz, K. A.; Grace, J. E.,
Jr.; Kolb, J.; Corsa, J.; Pierdomenico, M.; Jones, K.; Olson, R. E.; Macor, J. E.;
Albright, C. F. J. Pharmacol. Exp. Ther. 2008, 326, 502.
Zaczek, R.; Albright, C. F.; Toyn, J. H. J. Bio. Chem. 2008, 283, 22992.
20. Stachel, S. J.; Coburn, C. A.; Steele, T. G.; Jones, K. G.; Loutzenhiser, E. F.; Gregro, A.
R.; Rajapakse, H. A.; Lai, M.; Crouthamel, M.; Xu, M.; Tugusheva, K.; Lineberger, J.
E.; Pietrak, B. L.; Espeseth, A. S.; Shi, X.; Chen-Dodson, E.; Holloway, M. K.;
Munshi, S.; Simon, A. J.; Kuo, L.; Vacca, J. P. J. Med. Chem. 2004, 47, 6447.
21. Demont et al. also reported the sulfonamide substituted benzamides as BACE1
inhibitors, see: Demont, E. H.; Redshaw, S.; Walter, D. S. PCT Int. Appl. 2004 WO
2004/111022 A1.