N-Bridged bicyclic sulfonamides as inhibitors of γ-secretase

Article abstract of DOI:10.1016/j.bmcl.2009.10.060

The structural modification of a series of [3.3.1] bicyclic sulfonamide based γ-secretase inhibitors is described. Appropriate substitution on the bicyclic scaffold provides a significant increase in the metabolic stability of the compounds resulting in an improved in vivo metabolic profile.

Full text of DOI:10.1016/j.bmcl.2009.10.060

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6952–6956
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
N-Bridged bicyclic sulfonamides as inhibitors of c-secretase
a
a
a
a
a
Simeon Bowers a, , Gary D. Probst , Anh P. Truong , Roy K. Hom , Andrei W. Konradi , Hing L. Sham ,
Albert W. Garofalo a, Karina Wong b, Erich Goldbach b, Kevin P. Quinn b, John-Michael Sauer b,
William Wallace c, Lan Nguyen c, Susanna S. Hemphill c, Michael P. Bova c, Guriqbal S. Basi c
*
a Department of Medicinal Chemistry, Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, United States
b Department of Lead Finding, Drug Disposition, and Safety Evaluation, Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, United States
c Department of Biology, Elan Pharmaceuticals, 1000 Gateway Boulevard, South San Francisco, CA 94080, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The structural modification of a series of [3.3.1] bicyclic sulfonamide based
c-secretase inhibitors is
Received 23 July 2009
Revised 12 October 2009
Accepted 14 October 2009
Available online 30 October 2009
described. Appropriate substitution on the bicyclic scaffold provides a significant increase in the meta-
bolic stability of the compounds resulting in an improved in vivo metabolic profile.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Alzheimer’s disease
c
-Secretase inhibitor
Bicyclic sulfonamides
Alzheimer’s disease (AD) is the most prevalent form of demen-
tia and affects approximately 24 million people worldwide.1
Although the origin of the disease is not fully understood compel-
ling evidence suggests that the accumulation of b-amyloid (Ab)
peptide and the subsequent formation of amyloid plaques in the
cortex is responsible for neurodegeneration.2 Ab peptides are gen-
erated by cleavage of the b-amyloid precursor protein (b-APP) by
(F = 2.6%) in rat. In an attempt to improve the in vivo pharmacoki-
netic profile of this scaffold, we designed a series of analogs bearing
substitution on the non-pyrazole fused side of the [3.3.1] ring sys-
tem. It was reasoned that the highly lipophilic non-pyrazole fused
side of the [3.3.1] ring system would be susceptible to oxidative
metabolism and thus these modifications were designed to both
block potential sites of metabolism and to further reduce the lipo-
philicity of the scaffold.
two proteases, referred to as b-secretase and c-secretase and thus
inhibition of these enzymes is currently an important approach to-
Due to the accessibility of intermediate 3 the first series of com-
pounds that were synthesized involved adding substituents to the
C-10 carbon on the back of the [3.3.1] bicycle. These analogs were
all derived from a key intermediate, ester 6, which was prepared
from the known dialdehyde 2 as outlined in Scheme 1.7
The initial modifications of ester 6 are shown in Scheme 2.
Reduction of the ester provided alcohol 7 and basic ester hydrolysis
gave carboxylic acid 8. In order to present more hydrophobic sub-
stituents methyl and ethyl ethers 10 and 11 were prepared. Protec-
tion of the pyrazole NH of ester 6 with SEM-Cl followed by
reduction of the ester to the alcohol and subsequent O-alkylation
and final removal of the SEM protecting group gave the ethers 10
and 11. Ester 5 was also converted into cyclopropyl ether 14. Pro-
tection of the ketone of 5 followed by conversion of the ester to a
cyclopropyl alcohol under Kulinkovich conditions8 and subsequent
methylation gave compound 13 which was further elaborated into
pyrazole 14.
wards the development of disease modifying treatments for AD.3
A number of structurally diverse c-secretase inhibitorshave been
reported4 with several entering into clinical trials.5 In this Letter we
describe the structure–activity relationships of a series of N-bridged
bicyclic sulfonamides as inhibitors of
c
-secretase. Compound 16,
(Fig. 1) a representative member of the class, was developed during
hit expansion from micromolar hits identified from high throughput
screening of approximately 500 K small molecules. Compound 1 is a
potent inhibitor of
c-secretase (IC50 = 2 nM) in an in vitro assay
against recombinant APP substrate that measures potency of
compound for inhibition of Ab40 site cleavage in a partially enriched
enzyme extract from IMR-32 cells, but suffers from poor metabolic
stability and rapid glucuronide formation with only 15% of the
compound remaining after a 30 min incubation with mouse liver
microsomes (Table 1). This poor stability results in a short in vivo
half-life (24 min), rapid clearance, and low oral bioavailability
The influence of these substitutions on
c-secretase inhibition
and in vitro metabolic stability is shown in Table 1. Ester 6 retains
* Corresponding author. Tel.: +1 650 616 2630.
the single digit nanomolar potency of its parent 1 but alcohol 7 and
E-mail address: simeon.bowers@elan.com (S. Bowers).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.10.060

S. Bowers et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6952–6956
6953
Table 1
-Secretase inhibition, and metabolic stability for compounds 1–22
c
O
S
O
R
Cl
N
HN
N
Compdsa
R
GammaAPP IC50 (nM)
OxMet% remainingc (m, h)
GlucMet% remainingd (m, h)
b
1e
6
H
CO2Et
2
8
15, 48
0, 0
5, 0
0, 0
7
8
10
11
14
18
18entA
18entB
20
22
23
24
25
26
27
CH2OH
CO2H
CH2OMe
CH2OEt
Cyclopropyl methoxyl
CN
CN
CN
CF2H
CCH
678
8813
9
20
194
32
5957
13
4
0.75
0.52
2
1
26
1
na
na
89, 38
na
71, 28
85, 35
na
81, 45
na
na
24, 2
33, 2
na
na
37, 1
na
16, 40
4, 25
4, 12
74, 70
80, 72
86, 68
35, 40
27, 63
2, 42
3, 14
7, 6
CCMe
cis-CH@CHCl
trans-CH@CHCl
cis-CH@CHCF3
trans-CH@CHCF3
17, 38
36, 6
39, 2
a
b
c
Compounds are racemic unless stated otherwise.
See Ref. 11.
See Ref. 12.
See Ref. 13.
d
e
More active enantiomer.
O
O
O
O
S
Cl
S
O
O
10
Cl
S
Cl
OH
CO2H
GammaAPP IC50 = 2 nM
F = 2.6%, t1/2 = 24 min (rat)
N
1
H
H
N
a
b
N
8
6
HN
N
HN
N
HN
O
N
1
7
8
Figure 1. Representative N-bicyclic sulfonamide
c
-secretase inhibitor.
O
S
O
O
Cl
e, f
S
Cl
c, d
OR
OH
N
N
Ph
6
CO2Et
CO2Et
H
N
OEt
O
N
a
b
O
O
HN
N
SEMN
N
H
H
10 R = Me
11 R = Et
9
O
O
2
3
4
O
S
O
S
O
O
CO2Et
O
O
S
Cl
Cl
OMe
O
O
Cl
O
S
OMe
O
CO2Et
N
Cl
S
N
Cl
CO2Et
k, l
N
g
h, i, j
c
d, e
5
N
N
O
O
O
HN
N
HN
N
12
O
13
14
5
6
Scheme 2. Reagents and conditions: (a) LiBH4, THF, 60 °C, 2 h; (b) NaOH, H2O/THF,
rt, 4 h; (c) SEMCl, NaH, THF, 3 h, rt, 95%; (d) LiBH4, THF, 6 h, rt, quant.; (e) RI, NaH,
THF, 2 h, rt; (f) HCl, dioxane/H2O, 18 h, rt; (g) ethylene glycol, TMSCl, CH2Cl2, 50 °C,
2 days, 90%; (h) EtMgBr, Ti(OiPr)4, Et2O, rt, 18 h, 84%; (i) MeI, NaH, THF, rt, 18 h; (j)
HCl/dioxane, rt, 2 h, 96% (2 steps); (k) ethyl formate, NaOEt, THF/EtOH, 2 h, 40 °C; (l)
hydrazine monohydrate, AcOH, EtOH, 1 h, rt.
Scheme 1. Reagents and conditions: (a) acetone-1,3-dicarboxylic acid, BnNH2
NaOAc, HCl (aq), 3 days, rt, 40%; (b) Pd(OH)2/C, H2 (30 psi), CH3OH, 12 h, rt, quant.;
(c) 4-chlorobenzenesulfonyl chloride, Et3N, CH2Cl2, 2 h, rt, 88%; (d) ethyl formate,
NaOEt, THF/EtOH, 0.5 h, 60 °C, 94%; (e) hydrazine monohydrate, AcOH, EtOH, 1 h, rt,
97%.
acid 8 showed a significant loss of activity suggesting that polar
hydrogen bond donors in this region are not well tolerated. The
methyl and ethyl ethers (10 and 11, respectively) gain back the
potency and interestingly, these two ethers provide a significant
increase in the stability of the compounds towards glucuronide
formation. Cyclopropyl ether 14 lost potency compared to methyl
ether 10 suggesting that steric bulk in this region is not well
tolerated.

6954
S. Bowers et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6952–6956
O
S
Encouraged by this data further analogs were prepared. Ester 6
was converted into nitrile 18 via dehydration of an oxime derived
from aldehyde 16 (Scheme 3 and Scheme 4). Nitrile 18 demon-
O
O
O
S
Cl
b, c
Cl
CHO
N
N
N
a
strated reasonable
c-secretase inhibitory activity but also dis-
9
played a favorable improvement in oxidative and glucuronidation
stability across species. Separation of the enantiomers gave 18entB
which has good potency (13 nM) and improved in vitro oxidative
stability.
HN
N
N
SEM
21
22
CH3
Aldehyde 16 was also converted into difluoromethyl analog 20
upon treatment with DAST. Compound 20 retained the potency of
1 with a modest improvement in oxidative and glucuronidation
stability.
O
O
S
Cl
N
b, d, e
21
Further exploration of the structure activity relationships of this
regionwasmadewith alkynylanalogs22and23(Scheme5). Theter-
minal alkyne 22 was derived from aldehyde 21 upon treatment with
the Ohira–Bestmann reagent9 and propyne 23 was obtained upon
deprotonation of the terminal alkyne with LiHMDS followed by
quenching with methyl iodide. These analogs showed a significant
increase in potency over the parent compound 1 (23 IC50 = 0.52 nM)
but offered no advantages in terms of metabolic stability.
Since the alkynyl analogs 22 and 23 provided a significant in-
crease in gamma secretase inhibition, a number of alkenes were
prepared. Aldehyde 21 was converted into the cis- and trans-vinyl
chlorides and trifluoromethyl10 analogs as illustrated in Scheme 6.
In both cases the trans-isomers were more potent than the cis-iso-
mers. Interestingly, both trans-analogs 25 and 27 have similar
potency (IC50 = 1 nM) but the cis-analogs 24 and 26, possess an or-
der of magnitude difference in gamma secretase inhibition (24
IC50 = 2 nM and 26 IC50 = 26 nM). The trifluoromethyl analogs had
improved metabolic stability compared to the vinyl chlorides
although the stability was no improvement over the unsubstituted
parent compound 1.
HN
N
23
Scheme 5. Reagents and conditions: (a) oxalyl chloride, DMSO, Et3N, CH2Cl2,
À78 °C to rt, 2 h, 64%; (b) Ohira–Bestmann reagent, K2CO3, CH3OH, rt, 18 h 70%; (c)
HCl, dioxane/CH3OH, 1 h, 60 °C, 90%; (d) LiHMDS, CH3I, THF, À78 °C to rt, 4 h, 95%;
(e) HCl, dioxane/CH3OH, 4 h, 60 °C, quant.
O
S
O
S
O
Cl
O
Cl
Cl
Cl
N
N
a,b
21
HN
HN
N
N
24
25
O
S
O
O
O
CF3
Cl
S
Cl
CF3
N
N
c,d
21
Interestingly, the effect of substitution at the 10-position has a
profound effect upon the amount of the glucuronide formed in the
HN
N
HN
N
26
27
O
Scheme 6. Reagents and conditions: (a) ClCH2PPh3Cl, nBuLi, THF, 0 °C, 1 h, 53%; (b)
HCl/dioxane, CH3OH, 2 h, 60 °C,; (c) Ph2P(O)CH2CF3, TBAF, THF, À40 °C, 4 h, 12%; (d)
HCl/dioxane, CH3OH, 60 °C, 2 h.
O
O
CO2Et
O
CHO
Cl
S
Cl
S
a
b, c
N
N
6
in vitro assay (Table 1). It is presumed that the pyrazole NH is the
site of conjugation and it is intriguing that modification of the re-
mote 10-position would have such an effect. Although no clear
trend exists, the addition of substituents containing heteroatoms,
such as ethers 10 and 11 and nitrile 18, appear to substantially re-
duce the formation of glucuronides while the addition of hydrocar-
bon and halides seems to have a lesser effect (compounds 20, 22,
25 and 27). Although it appears that the addition of electron with-
drawing groups to the 10-position reduces the electron density and
nucleophilicity of the pyrazole nitrogen, electronic effects alone
cannot explain the observed SAR and the combination of steric
and electronic effects may determine the ability of the glu-
curonosyltransferases to recognize the compounds.
Since analogs bearing substitution on the carbon at the 10-posi-
tion of the bicyclic scaffold demonstrated that it is possible to in-
crease the in vitro metabolic stability of the inhibitors, it was
decided to expand the series by replacing this carbon atom with
a heteroatom. This replacement would both further lower the lipo-
philicity of the compounds and possibly provide further increases
in the potency of the inhibitors. The general route for the prepara-
tion of these compounds is depicted in Scheme 7. Ozonolysis of
furan 28 provided dialdehyde 30 which was elaborated to the mor-
pholine analog 32. Alternatively, the piperazine analog 34 was pre-
pared via dihydroxylation of pyrrolidine 29 followed by oxidative
cleavage to give dialdehyde 27 which was subsequently converted
into compound 34.
4-Cl-PhSO2N
N
4-Cl-PhSO2N
N
O
15
16
O
O
S
O
CN
Cl
S
Cl
CN
N
f
N
d, e
4-Cl-PhSO2N
N
HN
N
17
18
Scheme 3. Reagents and conditions: (a) 4-chlorobenzenesulfonyl chloride, pyri-
dine, rt, 1 h, quant.; (b) LiBH4, THF, rt, 2 h, 86%; (c) Dess–Martin periodinane,
NaHCO3, CH2Cl2, rt, 2 h, 87%; (d) NH2OHÁHCl, pyridine/EtOH, rt, 2 h; (e) MsCl, Et3N,
CH2Cl2, rt, 0.5 h; (f) NaOH, THF/H2O, rt, 5 h.
O
S
O
S
O
O
Cl
Cl
CHF2
CHF2
b
a
N
N
16
4-Cl-PhSO2N
HN
N
N
19
20
Scheme 4. Reagents and conditions: (a) DAST, CH2Cl2, 0 °C, 1 h; (b) NaOH, THF/H2O,
60 °C, 3 h 31% (2 steps).

S. Bowers et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6952–6956
6955
O
O
S
stability (Table 3). Separation of the enantiomers provided the ac-
tive enantiomer with an IC50 of 70 nM.
Thiomorpholine analog 48 was also synthesized starting from
the known ketone 45 (Scheme 9).14 N-Demethylation followed
by sulfonamide formation and conversion of the ketone into a
fused pyrazole gave compound 48 which demonstrates improved
Cl
O
a
O
O
X
d-h
28
N
X
H
H
Boc
N
30 X = O
31 X = NBoc
b, c
HN
N
c
-secretase activity over morpholine 32.
A select group of racemic compounds that displayed the most
32 X = O
33 X = NBoc
34 X = NH
29
i
favorable combination of c-secretase activity and metabolic stabil-
ity were separated by chiral HPLC. The more active enantiomer for
each compound was evaluated in rat to determine their in vivo
pharmacokinetic parameters, the results of which are summarized
in Table 4. It can be clearly seen that the improvements that were
made in the in vitro metabolic stability of nitrile 18 and morpho-
line 32 compared to the parent compound 1 resulted in an im-
proved in vivo pharmacokinetic profile with longer half-lives,
lower clearance and improved oral bioavailability.
Scheme 7. Reagents and conditions: (a) O3, CH2Cl2/CH3OH, 10/1, v/v, Ph3P, rt, 2 h;
(b) OsO4, NMO, acetone, rt, 18 h; (c) NaIO4, THF/H2O, rt, 3 h; (d) acetone-1,3-
dicarboxylic acid, BnNH2 NaOAc HCl (aq), 3 days, rt; (e) Pearlman’s catalyst, H2
(30 psi), CH3OH, 12 h, rt; (f) 4-chlorobenzenesulfonyl chloride, Et3N, CH2Cl2, 2 h, rt;
(g) ethyl formate, NaOEt, THF/EtOH, 0.5 h, 60 °C; (h) hydrazine monohydrate, AcOH,
EtOH, 1 h, rt; (i) HCl/dioxane, 2 h, rt.
In the nitrogen substituted series, piperazine 34 was converted
into a series of carbamates, ureas, amides and sulfonamides upon
treatment of 34 with the corresponding chloroformates, anhy-
drides, carbamoyl chlorides or sulfonamides as shown in Scheme
Table 2
c-Secretase inhibition, and metabolic stability for compounds 34–44
8. The c-secretase inhibition and metabolic stability for these ana-
logs are depicted in Table 2 and indicates that these piperazine
analogs are generally less potent than the piperidine analogs de-
O
O
Cl
S
R
N
scribed in Table 1. As with the previous series, the
c-secretase
N
inhibitory activity is dependent upon the size of the substituents
attached to the bicyclic ring system. This point is illustrated by
comparing the loss of activity in the series of carbamates as the
series moves from methyl (35) to ethyl (36), to isopropyl (37)
and to the tert-butyl carbamate 33. Interestingly, the carbamates
are much more potent than the amides, and the sulfonamides
possess only weak activity. In the absence of structural data the
poor activity of the amides is difficult to rationalize. Generally, a
heteroatom b to the 10-position results in favorable potency as is
seen with carbamate 35, ether 10 and nitrile 18 although this trend
does not hold for the most potent compounds reported in this ser-
ies, alkynes 22 and 23. In general, all of the piperazine analogs have
much improved oxidative and glucuronidation stability compared
to the carbon analogs described in Table 1 which may be attributed
to their overall lower lipophilicity.
HN
N
Compdsa
R
GammaAPP
OxMet%
remainingc
(m, h)
GlucMet%
remainingd
(m, h)
b
IC50 (nM)
34
33
35
36
37
38
39
40
41
42
43
44
H
6443
5722
66
202
1109
989
1066
826
175
5654
2510
4889
29, 37
19, 21
65, 83
39, 76
27, 53
na
85, 82
85, 86
56, 86
80, 84
77, 89
70, 98
89, 76
na
89, 72
99, 86
90, 48
na
94, 90
100, 98
na
96, 55
na
CO2tBu
CO2Me
CO2Et
CO2iPr
CO2CH2CH2OMe
C(O)CH3
C(O)Et
C(O)NMe2
SO2Me
SO2Et
Morpholine analog 32 demonstrated excellent in vitro meta-
bolic properties both in terms of oxidative and glucuronidation
SO2cPr
95, 34
a
b
c
Compounds are racemic unless stated otherwise.
See Ref. 11.
See Ref. 12.
See Ref. 13.
d
O
S
O
S
O
O
Cl
O
Cl
O
R
OR
a, b
N
N
N
N
c, d
g, h
34
Table 3
-Secretase inhibition, and metabolic stability for compounds 32 and 48
c
e, f
HN
HN
N
N
O
S
35 R = Me
36 R = Et
37 R = iPr
39 R = Me
40 R = Et
Cl
O
X
N
38 R = CH2CH2OMe
O
O
O
O
S
Cl
S
O
O
NMe2
Cl
S
O
HN
N
R
N
N
N
N
Compdsa
X
GammaAPP
IC50 (nM)
OxMet%
GlucMet%
remainingc (m, h)
remainingd (m, h)
b
HN
32
O
O
O
S
151
70
6277
26
80, 78
78, 81
75, 100
17, 47
100, 86
94, 71
93, 71
57, 0
N
HN
N
32entA
32entB
48
41
42 R = Me
43 R = Et
44 R = cPr
a
b
c
Compounds are racemic unless stated otherwise.
Scheme 8. Reagents and conditions: (a) ROC(O)Cl, Et3N, CH2Cl2, rt, 2 h; (b) NaOH,
THF/H2O, 3 h, 70 °C (c) (RCO)2O, pyridine, rt, 5 h; (d) NaOH, THF/H2O, 2 h, rt; (e)
N,N-dimethylcarbamyl chloride, Et3N, CH2Cl2, 2 days, rt; (f) NaOH, THF/H2O, 40 h,
70 °C; (g) RSO2Cl, Et3N, CH2Cl2, 1 h, rt; (h) NaOH, THF/H2O, 2 h, 60 °C.
See Ref. 11.
See Ref. 12.
See Ref. 13.
d

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Cl
O
H
N
Cl
O
S
S
S
N
S
a
b
c, d
N
N
15% in
2 steps
O
O
HN
N
O
47
48
45
46
Scheme 9. Reagents and conditions: (a) ACE, CH2Cl2, reflux, 6 h; (b) 4-chloro-
benzenesulfonyl chloride, Et3N, CH2Cl2, 2 h, rt, 15% (2 steps); (c) ethyl formate,
NaOEt, THF/EtOH, 0.5 h, 60 °C; (d) hydrazine monohydrate, AcOH, EtOH, 1 h, rt, 25%
(2 steps).
Table 4
Selected pharmacokinetic properties for compounds 1, 18 and 32
Compds
t1/2 (min)
Clearance (mL/h/kg)
AUC (nmol h/mL)
F%
1
18
32
24
61
69
2335
1707
1873
0.16
3.4
2.9
2
21
19
In summary, we have expanded the structure–activity relation-
ships of a series of N-bicyclic sulfonamide based -secretase inhib-
c
5. Siemers, E.; Skinner, M.; Dean, R. A.; Gonzales, C.; Satterwhite, J.; Farlow, M.;
Ness, D.; May, P. C. Clin. Neuropharmacol. 2005, 28, 126.
6. (a) The details of the discovery of compound 1 will be reported in due course;
(b) Bowers, S; Garofalo, A. W.; Hom, R. K.; Konradi, A. W.; Mattson, M. N.;
Neitzel, M. L.; Semko, C. M.; Truong, A. P.; Wu, J.; Xu, Y. Z. WO2007022502,
2007.
7. Gittos, M. W. Eur. Pat. Appl., EP330788, 1989.
8. (a) Kulinkovich, O.; Sviridov, S. V.; Vasilevski, D. A. Synthesis 1991, 234; (b)
Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100, 2789.
9. (a) Müller, S.; Liepold, B.; Roth, G.; Bestmann, H. J. Synlett 1996, 06, 521; (b)
Roth, G.; Liepold, B.; Müller, S.; Bestmann, H. J. Synthesis 2004, 1, 59; (c) Ohira,
S. Synth. Commun. 1989, 19, 561.
10. Yamamoto, S.; Sugimoto, H.; Tamura, O.; Mori, T.; Matsuo, N.; Ishibashi, N.
Tetrahedron 2004, 60, 8919.
itors. The introduction of substituents in one region of the bicyclic
scaffold resulted in improvements in the compounds’ metabolic
stabilities. These metabolic improvements were reflected in an im-
proved in vivo pharmacokinetic profile. The advances reported
here will allow further development of this series of compounds
as disease modifying agents in the treatment of Alzheimer’s
Disease.
Acknowledgments
11. Compound, initially diluted with DMSO, was incubated with gamma secretase
prepared from IMR-32 cell membranes. The reaction, at 37 °C, was initiated by
the addition of MBPC-125 Swedish substrate for two hours, and then quenched
by the addition of SDS. Quantification of cleaved substrate was determined by
an Ab40 specific ELISA assay. Values are means of three experiments.
We would like to thank Matthew Mattson, J. Labbe, Lanny Rus-
lim, David Nakamura, Heather Zhang, Bushan Samant, Michael Lee,
Terence Hui, Kevin Tanaka, Lany Ruslim, Pamela Keim, Jacek Jagod-
zinski, David Quincy, and Lee Latimer for their contributions to this
work.
12. Percentage of compound (1 lM) remaining after 30 min incubation in liver
microsomes (0.5 mg protein) supplemented with 1 mM NADPH at 37 °C in
phosphate buffer (m = mouse, h = human).
References and notes
13. Percentage of compound (2
lM) remaining after 30 min incubation in liver
microsomes (0.5 mg protein) supplemented with 1 mM UDPGA, 100 mM
MgCl2 and 50
h = human).
lg/mL alamethacin at 37 °C in phosphate buffer (m = mouse,
1. Ferri, C.; Prince, M.; Brayne, C.; Brodaty, H.; Fratiglioni, L.; Ganguli, M.; Hall, K.;
Hasegawa, K.; Hendrie, H.; Huang, Y. The Lancet 2005, 366, 2112.
2. Hardy, J.; Selkoe, D. J. Science 2002, 297, 353.
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