Triazoles as γ-secretase modulators

Article abstract of DOI:10.1016/j.bmcl.2011.04.089

Synthesis, SAR, and evaluation of aryl triazoles as novel gamma secretase modulators (GSMs) are presented in this communication. Starting from the literature and in-house leads, we evaluated a range of five-membered heterocycles as replacements for olefin

Full text of DOI:10.1016/j.bmcl.2011.04.089

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4083–4087
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Triazoles as
c
-secretase modulators
⇑
Christian Fischer , Susan L. Zultanski, Hua Zhou, Joey L. Methot, W. Colby Brown, Dawn M. Mampreian,
Adam J. Schell, Sanjiv Shah, Hugh Nuthall, Bethany L. Hughes, Nadja Smotrov, Candia M. Kenific,
Jonathan C. Cruz, Deborah Walker, Melanie Bouthillette, George N. Nikov, Dan F. Savage,
Valentina V. Jeliazkova-Mecheva, Damaris Diaz, Alexander A. Szewczak, Nathan Bays, Richard E. Middleton,
Benito Munoz, Mark S. Shearman
Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis, SAR, and evaluation of aryl triazoles as novel gamma secretase modulators (GSMs) are pre-
sented in this communication. Starting from the literature and in-house leads, we evaluated a range of
five-membered heterocycles as replacements for olefins commonly found in non-acid GSMs. 1,2,3-C-
aryl-triazoles were identified as suitable replacements which exhibited good modulation of c-secretase
activity, excellent pharmacokinetics and good central lowering of Ab42 in Sprague–Dawley rats.
Received 30 March 2011
Revised 18 April 2011
Accepted 21 April 2011
Available online 4 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Alzheimer
Secretase
GSM
Abeta lowering
Lead optimization
Alzheimer’s disease (AD) is a progressive neurodegenerative
disorder which in 2010 affected over 5 million patients in the US
alone.1 To date, only symptomatic treatments are available, which
provide short-term stabilization but have no effect on subsequent
disease progression. A widely accepted hypothesis for AD describes
oligomers of amyloid b Ab, and specifically the longer fragment
Ab42, as neurotoxic species. Such oligomers have led to cell death
and neurodegeneration in vitro and in vivo, causing symptoms
such as cognitive impairment.2
significantly greater neurotoxicity than their shorter counterparts
Ab36–Ab40.2 It has therefore been postulated that modulation of
the
not affecting total Ab levels, might be a safe approach to a dis-
ease-modifying therapy.8
-Secretase modulators (GSMs) modu-
c-cleavage to favor production of shorter fragments, while
c
late the cleavage of C-99 to decrease Ab42 and increase the
shorter Ab fragments (e.g., Ab37/389) whilst not affecting cleavage
of other substrates such as Notch.10
(R)-Flurbiprofen (Tarenflurbil, Flurizan™) (1, Fig. 1)11 is an
example of the first generation of carboxylic acid GSMs,12 and we
have previously reported the discovery and SAR of several exqui-
sitely selective (Ab IC50 40/42 > 100) classes of GSMs such as piper-
idine carboxylic acids 2.13 In the evolving arena of non-acid GSMs,
following the early work from Neurogenetics, Eisai disclosed aryl
imidazoles as represented by 3.14 In our own program aimed at
The ultimate step in the formation of Ab fragments3 is the pro-
teolytic cleavage of C-994 by the
c-secretase complex, wherein
presenilin acts as the protease which forms Ab fragments as well
as an intracellular domain (AICD).5 The molecular biology of
c
-secretase is complex and the intramembrane proteolysis of this
multi-component enzyme is poorly understood.6
-Secretase inhibitors (GSIs) have been studied for over a dec-
ade and several patents and publications have described the efforts
in this area.7 Inhibition of
-secretase has been associated with
mechanism-based side-effects linked to the processing of Notch,
one of several other substrates of -secretase. Such side-effects
c
identifying novel non-carboxylic acids as modulators of c-secre-
tase, we previously published our lead optimization strategy for
pyrimidine and purine derivatives (e.g., 4) as GSMs.15,16 Addition-
ally, we recently detailed the discovery of olefinic quinazolinones
(5) as GSMs, where we noted that the physicochemical properties
of such compounds were poor, hence limiting their oral
bioavailability.17
Following the discovery of quinazolinone GSMs (5), we sought
to identify related GSMs with improved solubility and oral expo-
sure in order to assess their in vivo PK/PD profile. Additionally,
compounds of the general structures 3 or 5 were also of concern
c
c
potentially limit the long-term use of GSIs.
An alternative approach to interrogate the amyloid hypothesis
came from the observation that the longer Ab42 fragment elicits
⇑
Corresponding author.
E-mail address: christian_fischer@merck.com (C. Fischer).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.04.089

4084
C. Fischer et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4083–4087
CO2H
Me
O
Me
F
MeO
N
CO2H
N
N
Ar
F
N
R1
R2
R2
Me
FlurizanTM (1)
E-2012 (3)
2
O
N
R1
N
R4
HN
R
N
MeO
N
N
H
N
R3
N
N
Me
Me
4
5
Me
Figure 1. Select gamma secretase modulators.
MeO
to us by virtue of their styrene moiety and we aimed to address
these concerns by replacing the olefin of compounds 5 with het-
erocycles (Fig. 2).18
boronates to form pyrazoles 16, for example. Nitrile 19 was con-
verted to oxadiazoles 20, tetrazoles 21, and 1,2,4-triazoles 22 by
standard condensation chemistry.
Initial studies were aimed at replacing the olefin with simple
five-membered heterocycles, which were readily accessible from
commercially available starting materials. C-aryl triazoles were
prepared according to Schemes 1, and 2 describes a range of addi-
tional heterocycles that were synthesized.
In Scheme 1, alkyl azides were generally prepared from the cor-
responding halide or pseudohalide and sodium azide in polar apro-
tic solvents at room temperature. Aldehyde 8 was readily prepared
from commercially available 4-fluoro-3-methoxybenzaldehyde (7)
and 4-methyl-1H-imidazole with potassium carbonate as the inor-
ganic base and heating overnight in DMF. Separation of the unde-
sired regioisomer was achieved through a wash procedure and
subsequent purification on silica gel.19
Alkynylation of aldehyde 8 with the Bestmann–Ohira reagent
gave the desired alkyne 9 in quantitative yield. The click reaction
of alkyne 9 with azides in ethanol/water with copper(II)sulfate
and sodium ascorbate as the reductant furnished triazoles 10 in
good to excellent yields.20
Other heterocylic GSMs were prepared as described in Scheme
2 by standard cross-coupling and condensation chemistry from
commercially available materials.
During the course of this initial exploration, a wide range of het-
erocyclic GSMs were prepared according to the general chemistry
described in Schemes 1 and 2. Cell biochemical data for selected
examples are reported in Table 1.21
Our initial set of five-membered ring heterocyclic replacements
revealed a strong preference for triazoles and particularly C-aryl-
linked 1,2,3- and 1,2,4-triazoles. Further evaluation and screening
of both 1,2,3- and 1,2,4-triazoles revealed very similar potencies
and modulation potential for both scaffolds, however 1,2,3-tria-
zoles consistently preformed better in vivo (data not shown). After
establishing 1,2,3-triazoles as a viable replacement for the olefin in
compounds 3 or 5, we proceeded to explore the SAR of this new tri-
azole series. Rapid exploration of the chemical space was aided by
a convergent click chemistry approach from alkyne 9 and azides
under Cu-catalysis (see Scheme 1).22
We initially proceeded to examine the SAR around benzyl tria-
zole 23. Substitution in the meta- and para-positions gave a boost
in potency, with 4-substituted and 3,5-disubstituted benzylic tria-
zoles being the most promising in terms of potency (Table 2).
Compound 39 displayed particularly potent GSM activity with
an excellent window over Notch (IC50 > 50 lM; >100-fold selec-
SNAr of compounds 11 and 18 with 2-methyl-imidazole fur-
nished the corresponding building blocks 12 and 19. Nitro com-
pound 12 was further reduced and then diazotized and treated
with sodium bromide or sodium azide to form bromide 13a and
azide 13b, respectively. Azide 13b was then converted to the N-aryl
triazoles 17 under standard click conditions (vide supra).
Oxadiazoles 15 were prepared from bromide 13a in a two-step
procedure that involved carbonylation and trapping with acylhyd-
razides followed by cyclodehydration. Bromide 13a was also used
as a starting material in Suzuki reactions with heteroaromatic
tive).23 Consequently, we decided to further profile compound 39
in vivo. Initial PK studies in Sprague–Dawley (SD) rats established
an excellent profile and triazole 39 was taken into an acute PK/PD
experiment to assess brain penetration and Ab42 lowering (Fig. 3).
Six hours after an oral dose of 100 mg/kg in SD rats, an excellent
plasma and brain exposure (brain to plasma ratio 1.2:1) was
achieved and we were delighted to observe a significant reduction
of whole brain Ab42 levels.
While triazoles 31–39 (Table 2) showed a substantial improve-
ment in potency relative to our initial screening hit 23, we also
O
A
A
A
HN
R
R
A
MeO
N
MeO
A
N
N
N
N
5
6
Me
Me
Figure 2. Olefin replacement strategy.

C. Fischer et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4083–4087
4085
H
MeO
N
CHO
MeO
N
MeO
F
CHO
Methylimidazole
K2CO3, MeOH
N
K2CO3, DMF, Δ
Bestmann reagent
N
7
8
9
Me
Me
N
N
N
9
CuSO4,
NaN3
MeO
Na-ascorbate
R
X
R
N3
R
DMF or DMSO
EtOH/H2O
N
N
10
Me
Scheme 1. Synthesis of C-aryl-1,2,3-triazole GSMs.
observed an increased binding to the hERG channel. Encouraged by
the in vivo activity of compound 39, we proceeded to further
optimize this series with a particular focus on reducing the hERG
liability. We speculated that the hydrophobic benzyl substituents
MeO
NO2
MeO
N
X
MeO
Br
NO2
Methylimidazole
1) H2/Pd/C
2) NaNO2
N
N
K2CO3, DMF, Δ
N
13a
for
: NaBr
13a
X = Br
13b X = N3
11
12
Me
for 13b: NaN3
Me
H
N
R1
O
N
N
H
N
H2N
R1
R1
MeO
N
Br
MeO
N
MeO
N
H
O
O
C2Cl6, PPh3
Herrmann's Pd-cycle
O
N
N
N
N
NEt3, DCM
[(t-Bu)3PH]BF4
Mo(CO)6, DBU, THF
13a
14
15
Me
Me
Me
N
N
R2
MeO
Br
Pd2(dba)3/PCy3
K3PO4
MeO
N
N R2
+
N
N
N
N
(RO)2B
Dioxane/Water
13a
16
Me
Me
N
N
N
R3
MeO
MeO
N
N3
CuSO4,
Na-ascorbate
+
H
R3
N
N
N
EtOH/H2O
13b
17
Me
Me
O
N
N
R4
MeO
1) HONH3Cl, NaHCO3
H2O, EtOH
N
N
O
N
2)
20
R4
Et3N, DMF
Cl
Me
N
R5
N
MeO
N
CN
MeO
N
N
MeO
CN
Methylimidazole
1) NaN3, ZnBr2, DMF, Δ
N
K2CO3, DMF, Δ
N
F
2) R5Br, K2CO3, THF
18
19
21
Me
Me
N
N
O
R6
MeO
N
NH2
N
R6
N
H
H
N
K2CO3, n-BuOH
22
Me
Scheme 2. Synthesis of representative heterocyclic GSMs.

4086
C. Fischer et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4083–4087
Table 1
Table 2 (continued)
Screen of heterocyclic replacements
Compound
R
Ab42 IC50
M)
Ab40 IC50
M)
hERG IC50
M)
MeO
R
(
l
(
l
(l
t-Bu
Br
N
N
36
0.45
0.32
1.71
2.77
0.32
0.10
Me
t-Bu
Br
Compound
R
Ab42 IC50
(l
M)
Ab40 IC50 (lM)
37
N
N
N
N
23
1.44
8.10
CF3
N
N
Me
Si
Me
38
39
0.22
0.30
1.19
4.80
0.39
0.39
24
25
1.94
7.06
7.61
>10
Me
CF3
N
N
Me
Si
Me
Me
N
t-Bu
N
N
All compounds were tested at least twice in independent experiments (at least once
for hERG). For a description of the assay conditions. See Refs. 21,24.
26
27
>10
>10
>10
N
O
7.01
N
N
N
N
Dose (iv; po) (mg/kg)
Clp (mL/min/kg)
Vdss (L/Kg)
t½ (iv) (h)
1; 2
24
7.1
7.7
41
PK/PD assessment 6 hours after
an oral dose of 100 mg/kg (n=5)
28
29
30
5.71
>10
>10
>10
3.01
N
N
[Plasma] = 47 μM; [Brain] = 56 μM
Aβ42 (brain): -48 %
N
%F
O
N
AUCN 0−24 po (μM h kg/mg) 1.4
NH
0.78
Figure 3. SD rat PK and PK/PD assessment of triazole 39.
N
All compounds were tested at least twice in independent experiments. For a
description of the assay conditions. See Ref. 21.
on the triazole were responsible for the increase in hERG binding24
and proceeded to look for suitable replacements of the phenyl
group as well as introduction of polar functionality (Table 3).
Table 3
Modulation of Ab40/42 processing by triazoles 40–47
N
N
N
R
Table 2
MeO
N
Modulation of Ab40/42 processing by triazoles 31–39
N
N
N
N
R
MeO
N
Me
N
Me
Compound
R
Ab42
IC50
Ab40
IC50
hERG
IC50
(
lM)
(lM)
(lM)
Compound
R
Ab42 IC50
Ab40 IC50
hERG IC50
M)
N
(lM)
(lM)
(l
40
41
0.82
1.41
4.04
>10
5.43
>10
F
31
2.64
>10
2.49
N
N
F
32
33
1.44
1.22
6.24
>10
2.70
2.19
Me
N
O
42
43
1.64
1.00
6.61
5.46
>10
8.1
F
CF3
N
N
34
35
0.49
0.44
6.02
2.53
1.25
0.72
OCF3
Me
N
O

C. Fischer et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4083–4087
4087
5. (a) Li, H.; Wolfe, M. S.; Selkoe, D. J. Cell Struct. 2009, 17, 326; (b) Osenkowski, P.;
Li, H.; Ye, W.; Li, D.; Aeschbach, L.; Fraering, P. C.; Wolfe, M. S.; Selkoe, D. J.; Li,
H. J. Mol. Biol. 2009, 385, 642.
6. See for example: (a) Selkoe, D. J.; Wolfe, M. S. Cell 2007, 131, 215; (b) Wolfe, M.
S. Curr. Top. Med. Chem. 2008, 8, 2; (c) Steiner, H.; Fluhrer, R.; Haass, C. J. Biol.
Chem. 2008, 283, 29627; (d) Wolfe, M. S. Semin. Cell Dev. Biol. 2009, 20, 219.
7. For selected reviews, see: (a) Wu, W.-L.; Zhang, L. Drug Dev. Res. 2009, 70, 94;
(b) Olson, R. E.; Albright, C. F. Curr. Top. Med. Chem. 2008, 8, 17; (c) Imbimbo, B.
P. Drug Discovery Today 2008, 5, 169; (d) Zettl, H.; Weggen, S.; Schneider, P.;
Schneider, G. Trends Pharmacol. Sci. 2010, 31, 402.
Table 3 (continued)
Compound
R
Ab42
IC50
Ab40
IC50
hERG
IC50
(lM)
(lM)
(l
M)
N
44
0.82
7.60
>10
4-Py
N
O
8. For a recent review on secretase biology and modes of c-secretase inhibition/
modulation, see: De Strooper, B.; Vassar, R.; Golde, T. Nat. Rev. Neurol. 2010, 6,
99.
S
45
46
0.27
0.41
0.77
1.13
2.15
>10
9. All GSMs lower Ab42 selectively over Ab40, however, some raise the levels of
Ab38 others Ab37. The consequence of this difference is unknown.
10. For selected reviews on GSMs, see: (a) Peretto, I.; La Porta, E. Curr. Top. Med.
Chem. 2008, 8, 38; (b) Breher, D. Curr. Top. Med. Chem. 2008, 8, 34; (c) Imbimbo,
B. P. Curr. Top. Med. Chem. 2008, 8, 54; (d) Tomita, T. Expert Rev. Neurother.
2009, 9, 661.
11. Flurizan is the COX-inactive (COX1&2) enantiomer of (S)-Flurbiprofen.
12. For a recent comprehensive review of the GSM chemical space, see: Oehlrich,
D.; Berthelot, D. J.-C.; Gijsen, H. J. M. J. Med. Chem. 2011, 54, 669.
13. (a) For patents in this area, see: (a) Hannam, J. C.; Hartmann, S.; M., Andrew; R.,
Mark P. WO2007110667.; (b) Madin, A.; Ridgill, M. P.; Kulagowski, J. J. WO
2007116228.; (c) Garcia, Y.; Hannam, J. C.; Harrison, T.; Hamblett, C. L.; Hubbs,
J. L.; Kulagowski, J. J.; Madin, A.; Ridgill, M. P.; Seward, E. WO 2007125364.; (d)
Stanton, M. G.; Munoz, B.; Sloman, D. L.; Hubbs, J. L.; Hamblett, C. L. WO
2008030391.; (e) Munoz, B.; Hubbs, J. L.; Hamblett, C. L.; Zhou, H.; Martinez, M.
WO 2008085301.
14. For a key patent, see: Kimura, T.; Kawano, K.; Doi, E.; Kitazawa, N.; Shin, K.;
Miyagawa, T.; Kaneko, T.; Ito, K.; Takaishi, M.; Sasaki, T.; Hagiwara, H. WO
2005115990.
15. (a) Blurton, P.; Fletcher, S.; Teall, M.; Harrison, T.; Munoz, B.; Rivkin, A.;
Hamblett, C.; Siliphaivanh, P.; Otte, K. WO 2008099210.; (b) Rivkin, A.; Ahearn,
S. P.; Chichetti, S. M.; Hamblett, C. L.; Garcia, Y.; Martinez, M.; Munoz, B. WO
2010019392.
16. (a) Rivkin, A.; Ahearn, S. P.; Chichetti, S. M.; Kim, Y. R.; Li, C.; Rosenau, A.;
Kattar, S. D.; Jung, J.; Shah, S.; Hughes, B. L.; Crispino, J. L.; Middleton, R. E.;
Szewczak, A. A.; Munoz, B.; Shearman, M. S. Bioorg. Med. Chem. Lett. 2010, 20,
1269; (b) Rivkin, A.; Ahearn, S. P.; Chichetti, S. M.; Hamblett, C. L.; Garcia, Y.;
Martinez, M.; Hubbs, J. L.; Reutershan, M. H.; Daniels, M. H.; Siliphaivanh, P.;
Otte, K. M.; Li, C.; Rosenau, A.; Surdi, L. M.; Jung, J.; Hughes, B. L.; Crispino, J. L.;
Nikov, G. N.; Middleton, R. E.; Moxham, C. M.; Szewczak, A. A.; Shah, S.; Moy, L.
Y.; Kenific, C. M.; Tanga, F.; Cruz, J. C.; Andrade, P.; Angagaw, M. H.; Shomer, N.
H.; Miller, T.; Munoz, B.; Shearman, M. S. Bioorg. Med. Chem. Lett. 2010, 20,
2279.
17. Fischer, C.; Shah, S.; Hughes, B. L.; Nikov, G. N.; Crispino, J. L.; Middleton, R. E.;
Szewczak, A. A.; Munoz, B.; Shearman, M. S. Bioorg. Med. Chem. Lett. 2011, 21,
773.
18. Fischer, C.; Munoz, B.; Zultanski, S.; Methot, J.; Zhou, H.; Brown, W. C.
WO2008156580.
S
N
47
0.20
2.06
>10
O
All compounds were tested at least twice in independent experiments (at least once
for hERG). For a description of the assay conditions. See Refs.21,24
Dose (iv; po) (mg/kg)
Clp (mL/min/kg)
Vdss (L/Kg)
t½ (iv) (h)
%F
1; 2
13.7
2.8
5.4
49
PK/PD assessment 6 hours after
an oral dose of 60 mg/kg (n=5)
[Plasma] = 40 μM; [Brain] = 9.4 μM
Aβ42 (brain): -42%
AUCN 0−24 po (μM h kg/mg)
2.6
Figure 4. SD rat PK and PK/PD assessment of triazole 47.
Gratifyingly, both strategies led to a significant attenuation of
hERG binding while maintaining good on-target potency and GS
modulation. In particular, compound 47 stood out as one of the
most potent compounds in this series, accompanied with reduced
binding to the hERG channel. Further evaluation of triazole 47 re-
vealed an acceptable overall profile without affecting the process-
ing of Notch (IC50 > 50 lM; >100-fold selective). The in vivo rat PK
profile of triazole 47 was sufficient for further profiling in rat PK/PD
studies and we were pleased to observe central Ab42 lowering 6 h
after a 60 mg/kg dose in SD rats (Fig. 4). However, brain exposure
and the brain to plasma ratio25 were significantly lower compared
to compound 39.
19. Careful work-up and purification was necessary to remove the unwanted
regioisomer. See Ref. 18 for detailed synthetic procedures.
20. Other analogues were prepared in a similar manner. For detailed synthetic
procedures, see Ref. 18.
21. IC50 measurements for Ab40 and Ab42 were determined using
electrochemiluminescent detection of peptides secreted by SH-SY5Y cells
stably overexpressing the b-APP C-terminal fragment SPA4CT. All compounds
were tested at least twice in independent experiments.
In summary, we have reported the discovery and SAR of tria-
zoles as modulators of
c-secretase. Starting from the initial lead
Consistent with the profile of
were constant; selected GSMs were confirmed in
c
-secretase modulators, total Ab peptide levels
SELDI experiment
a
benzyl triazole 23, we proceeded to optimize potency, brain pene-
tration and hERG binding. We found that the selectivity of Ab42
over Ab40 was generally moderate (5- to 20-fold), which is consis-
tent with other non-acid GSMs of this type.14 However, compounds
in this series behaved as GSMs26 and the selectivity over Notch
processing was generally very high (>100-fold), irrespective of
the Ab 42/40 ratio. During the course of this optimization program
we identified several potent and selective GSMs with in vivo PD
activity upon oral dosing. Future directions in this series and novel
strategies for non-acid GSM will be reported in due course.
confirming the appearance of shorter fragments while Ab42 formation was
suppressed. (a) Best, J. D.; Jay, M. T.; Otu, F.; Ma, J.; Nadin, A.; Ellis, S.; Lewis, H.
D.; Pattison, C.; Reilly, M.; Harrison, T.; Shearman, M. S.; Williamson, T. L.;
Atack, J. R. J. Pharmacol. Exp. Ther. 2005, 313, 902; (b) Clarke, E. E.; Shearman, M.
S. J. Neurosci. Methods 2000, 102, 61; (c) Dyrks, T.; Dyrks, E.; Monning, U.;
Urmoneit, B.; Turner, J.; Beyreuther, K. FEBS Lett. 1993, 335, 89.
22. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004.
23. Not all compounds were profiled in our Notch nuclear translocation assay.
Most compounds maintain a significant window over Notch. Key compounds
were profiled in the following assay: HeLa cells were made to co-express
nonfunctional halves of luciferase, one fused to Notch
-Secretase mediated cleavage of Notch E results in release of Notch
intracellular domain (NICD)/N-terminal luciferase, which translocates to the
nucleus and binds the RBP-J /C-terminal luciferase to form functional
DE and the other to RBP-
Jj.
c
D
j
a
References and notes
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detect NICD levels by measuring total luminescence upon addition of luciferin
to lysed cells. Paulmurugan, R.; Gambhir, S. S. Anal. Chem. 2005, 77, 1295.
24. For a description of the hERG radioligand displacement assay, see: Butcher, J.
W.; Claremon, D. A.; Connolly, T. M.; Dean, D. C.; Karczewski, J.; Koblan, K. S.;
Kostura, M. J.; Liverton, N. J.; Melillo, D. G. WO 200205860.
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28, 11950; (b) Moreno, H.; Yu, E.; Pigino, G.; Hernandez, A. I.; Kim, N.; Moreira,
J. E.; Sugimori, M.; Llinas, R. R. PNAS 2009, 106, 5901.
3. Thinakara, G.; Koo, E. H. J. Biol. Chem. 2008, 283, 29615.
4. C-99 is the C-terminal fragment of APP, which is formed from APP by BACE1
mediated proteolysis.
25.
A
modest PgP susceptibility (rat-mdr1a BA/AB = 7.2) might be partially
responsible for the lower brain exposure of compound 47.
26. The reduction of Ab42 in PK/PD experiments was generally greater than the
reduction of Ab40, consistent with in vitro findings.