Piperidine-derived γ-secretase modulators

Article abstract of DOI:10.1016/j.bmcl.2009.08.072

This Letter details the SAR of a novel series of piperidine-derived γ-secretase modulators. Compound 10h was found to be a potent modulator in vitro, which on further profiling, was found to decrease Aβ42, increase Aβ38 and have no effect on Aβ40 levels.

Full text of DOI:10.1016/j.bmcl.2009.08.072

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1306–1311
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Piperidine-derived c-secretase modulators
a
a
a
b
a
Adrian Hall a, , Richard L. Elliott , Gerard M. P. Giblin , Ishrut Hussain , James Musgrave , Alan Naylor ,
*
Rosemary Sasse b, Beverley Smith a
a Neurosciences Centre of Excellence for Drug Discovery, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
b Department of Screening & Compound Profiling, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter details the SAR of a novel series of piperidine-derived c-secretase modulators. Compound 10h
Received 12 June 2009
Revised 19 August 2009
Accepted 20 August 2009
Available online 23 August 2009
was found to be a potent modulator in vitro, which on further profiling, was found to decrease Ab42,
increase Ab38 and have no effect on Ab40 levels. Furthermore, 10h demonstrated excellent pharmacoki-
netic parameters in the mouse, rat and dog in addition to good CNS penetration in the mouse.
Ó 2009 Published by Elsevier Ltd.
Alzheimer’s disease (AD) is a devastating neurological disorder
with bleak prognosis that results in cognitive impairment and loss
of brain mass.1 At present only the cognitive aspects of AD can be
treated, thus novel treatments that slow or halt disease progres-
sion are highly desirable. AD was first characterised in 1906 by
Alois Alzheimer following pathological examination of brain tis-
sue.2 This analysis revealed two underlying disease components,
neurofibiliary tangles, composed of hyperphosphorylated tau pro-
tein, and amyloid plaques.3 The latter are thought to be causative
of the disease and consist of amyloid-beta (Ab) peptides of 40–42
amino acids (Ab40 and Ab42, respectively).4 Literature suggests
that Ab42 is the major pathogen, is less soluble than Ab40 and
seeds plaque formation, whereas Ab40 does not initiate plaque for-
mation itself but is a constituent of plaques.4 These peptides are
produced from amyloid precursor protein (APP) by the sequential
been evaluated in phase 3 clinical trials for AD.10 These derivatives
have been shown to modulate, rather than inhibit, the action of
c
-secretase.11 Thus they shift the cleavage of
c-secretase to pro-
duce shorter, less pathogenic peptides such as Ab40 and Ab38.12
In so doing, modulators do not alter the rate of enzyme processing
or cause a build up of substrate.13 Thus, substrates such as Notch
are still processed and can effect their downstream signaling which
should result in modulators having a better toxicological profile.
However, one drawback has been that these compounds generally
have weak in vitro activity and thus achieving sustained levels of
compound in the brain to modulate
Thus, new more potent -secretase modulators offer the potential
c
-secretase is challenging.10,14
c
of slowing or halting AD progression without the side effects asso-
ciated with inhibitors.
We were interested in identifying novel, potent,
c-secretase
action of b-secretase and
been invested to identify inhibitors of either enzyme to reduce
Ab production.5 Several inhibitors of
-secretase have been identi-
fied, such as LY-4501396 (1, Fig. 1) and progressed through toxico-
logical and clinical studies. Studies with -secretase inhibitors
have uncovered several toxicological issues as it has been discov-
ered that -secretase processes a number of substrates and in par-
c
-secretase, thus a significant effort has
modulators for the treatment of AD. Literature analysis revealed
several carboxylic acid-derived templates, a selection of which is
depicted in Figure 2. We were particularly interested in piperidine
derivatives such as 5 and 6.15 Although still extremely lipophilic
these compounds appeared less lipophilic than compounds such
as 316 and 4.17 Thus, we sought to synthesise and test novel com-
c
c
c
ticular, inhibition of Notch processing has been found to manifest
in toxicity of the gastrointestinal (GI) and immune system.7
Epidemiological analysis has shown that certain non-steroidal
anti-inflammatory drugs (NSAIDs) lower the risk of developing
AD.8 Further analysis has shown this effect is independent of cyclo-
oxygenase (COX) inhibition. NSAID derivatives devoid of COX inhi-
bition,9 such as tarenflurbil (MPC-7869, FlurizanTM), 2 (Fig. 1) have
N
OH
O
O
O
NH
N
H
F
H
O
O
1, LY-450139
2, flurbiprofen
* Corresponding author at present address: Neuroscience Product Creation Unit,
Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire
AL10 9SN, UK. Tel.: +44 1279627539.
Figure 1. Structures of
c-secreatase inhibitor LY-450139 (1) and a c-secretase
E-mail address: adian_hall@eisai.net (A. Hall).
modulator tarenflurbil (2).
0960-894X/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2009.08.072

A. Hall et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1306–1311
1307
pure piperidine 9. The absolute configuration of 9 was confirmed
by X-ray crystallographic analysis of the (
)-(À)-mandelic acid salt.
D
Piperidine 9 was then subjected to reaction with various alde-
hydes to give the corresponding imine which was subsequently
trapped with benzotriazole followed by addition of organozinc re-
agents (which were either commercially available or could be pre-
pared from the corresponding organomagnesium derivatives) to
give compounds such as 10h, upon ester saponification (Scheme
1).18
OH
O
OH
O
O
F3C
Compounds were incubated with SHSY5Y19 cells overexpress-
ing human APP Swedish variant for 48 h. The levels of Ab42 and
Ab40 were determined by enzyme-linked immunosorbent assay
(either Meso Scale Discovery [MSD] or AlphaLISA).20 Compounds
were also cross-screened for their ability to inhibit Notch
processing.20
CF3
CF3
3
4
OH
OH
X
O
O
N
N
In the first round of structure–activity relationship (SAR) inves-
tigation we chose the trifluoromethylpyridyl unit as a starting
point as 6-trifluoromethylpyridine-3-carbaldehyde was commer-
cially available (Table 1). We were pleased to find that derivatives
such as 10a were moderately active at reducing Ab42 secretion in
our whole cell assay. Furthermore, we found that increasing the
size of the R-group led to increased in vitro potency (10b–i) with
maximal potency achieved with a 4–6 carbon unit. Introduction
of an oxygen atom significantly reduced activity (compare 10g to
10j). Cyclic hydrocarbons were also active (10k) but aromatic sub-
stituents such as substituted phenyl (10l) and benzyl (10m) or
phenethyl (10n) were slightly less active (Table 1).
R
F3C
CF3
CF3
c-secretase modulators from patent application
5
6
Figure 2. Selection of acetic acid
the literature.
pounds with heterocyclic aromatic groups on the 1-position of the
piperidine to further lower lipophilicity.
The synthesis of compounds is shown in Scheme 1, as exempli-
fied by compound 10h.18 2-Chloro-4-methylpyridine underwent
Suzuki reaction with 4-trifluoromethylbenzene boronic acid to give
7. Deprotonation of 7 and trapping with dimethylcarbonate gave
ester 8. Reduction of pyridine 8 gave the corresponding racemic
Having identified several R-groups which provided good levels
of in vitro potency, we selected the iso-amyl group and fixed this
whilst we varied the pyridine with alternative aromatic heterocy-
cles (Table 2). Initially we maintained the trifluoromethyl group in
the 4-position relative to the connection point. Thus isomeric pyr-
idine 11a, containing a more basic nitrogen atom, was well toler-
cis-piperidine which underwent crystallization first with (
L)-(+)-
mandelic acid then (
D
)-(À)-mandelic acid to give enantiomerically
ated. Addition of
a
second N-atom to give pyridazine 11b
N
O
O
b
Cl
B
a
N
N
HO
OH
8
CF3
CF3
CF3
7
c, d
F3C
N
OH
O
N
O
e, f, g
HN
O
9
CF3
10h
CF3
Scheme 1. Conditions and reagents: (a) PdCl2 (dppf)ÁCH2Cl2 (cat.), 1,2-dimethoxyethane, reflux, 20 h; 81%; (b) LDA, THF, À70 °C, 1 h, then dimethyl carbonate, À70 °C 10 min.
then warm to rt, 89%; (c) PtO2 (cat.), 4 N HCl in dioxane, MeOH, H2, 50 °C, 50 psi, 3 h, 99%; (d) ( )-(+)-mandelic acid, i-PrOH, filtration and evaporation, (
L
D
)-(À)-mandelic acid, i-
PrOH then CH2Cl2–2M Na2CO3, 38%; (e) 6-(trifluoromethyl)-3-pyridinecarbaldehyde, benzotriazole, PhMe, reflux (Dean–Stark), 5 h then evaporation; (f) DCM, 1-ZnX-3-
methylbutane in Et2O (X = Cl or Br, see Supplementary data for full details), 0 °C then rt 16 h; (g) 2 M NaOH, MeOH, 60 °C, 10 h.

1308
A. Hall et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1306–1311
Table 1
In vitro SAR for compounds 1, 3 and 4 and 10a–n
O
F3C
N
Na+
N
O
R
CF3
10a-n
Ab40 pIC50 (%inhibition)b
Notch pIC50 (%inhibition)b
a
a
a
Compds
R
Ab42 pIC50
1
3
4
n/a
n/a
n/a
Et
i-Pr
c-Pr
n-Bu
i-Bu
CH2-c-Bu
n-Pentyl
i-Amyl
n-Hex
–(CH2)3–OMe
Cyhex
p-CF3phenyl
CH2Ph
CH2CH2Ph
7.4 0.13
5.4 0.26c
5.7e
7.4 0.13
64.8 (32)d
<4.7 (13)
<4.7 (20)
<4.7 (24)
4.3 0.10
4.8 0.11
4.5 0.07
5.5 0.01
5.1 0.48
5.2 0.72
4.8 0.06
4.5 0.07
4.6 0.02
64.8 (33)d
5.0 0.18
<4.7 (40)h
6.5 0.18
<4.7 (20)
<4.7 (23)
<4.7 (10)
<4.7 (21)
<4.7 (23)
<4.7 (33)
<4.7 (25)
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
5.0 0.14
5.4 0.17
5.1 0.14
6.2 0.15
6.2 0.09
6.6 0.07
5.9 0.16
6.5 0.33
6.3 0.12
5.0 0.15
5.4 0.22
5.9 0.21
5.8 0.18
5.7 0.24
<4.7 (17)e,
f
4.8 0.03
<4.7 (24)e,
f
5.3 0.45
<4.7 (10)
ntg
5.1 0.03
<4.7 (34)
<4.7 (32)
a
b
c
Values are means of at least two experiments standard deviation.
%Inhibition at 20 M.
IC50 = 3.98 M, lit. IC50 1–10
Single experiment giving pIC50 4.8, all other experiments gave pIC50 <4.7.
Single experiment.
Single experiment giving pIC50 excluded as max asymtote <40%.
nt = not tested.
Two pIC50 values excluded as the asymptote maximums were very partial (ꢀ50%).
l
l
lM.
d
e
f
g
h
resulted in a slight decrease in potency. However, pyrimidine 11c
restored activity whereas pyrimidine isomer 11d showed activity
intermediate between 11b and 11c. The pyrazine derivative 11e
also displayed activity. Compounds 11f–i demonstrated that the
trifluoromethyl group could be moved around the ring or could
be replaced by small alkyl groups. Although the majority of com-
pounds had no effect on Notch processing (pIC50 <4.7), some com-
pounds such as 11a and 11i did exhibit weak activity against Notch
processing. However, these compounds were significantly more
potent at inhibiting Ab42 production.
Further profiling of a selection of compounds in a cell based as-
say (24 h incubation)20 demonstrated a modulatory profile. Levels
of Ab42 were decreased in a concentration-dependent manner,
whilst levels of Ab38 were increased in a concentration-dependent
manner and Ab40 levels were unaffected (Table 3). Compounds
also had no effect on total Ab levels indicating the rise in Ab38
compensates for the decrease in Ab42. This is in contrast to the
profile of inhibitors such as 1 (LY-450139) which decreases levels
of all Ab species (and therefore total Ab). Furthermore, the com-
pounds described in Table 3 were found not to be cytotoxic. Com-
CYP inhibitors. Based on these data, compounds 10h and 11d
emerged as the most interesting compounds, their in vivo pharma-
cokinetic profiles are listed in Table 4. Compounds 10h and 11d
demonstrated low clearance and excellent bioavailability in the
rat and dog. Compound 10h was also profiled in the mouse where
the pharmacokinetic parameters were found to be similar to the
rat and dog, thus demonstrating consistent pharmacokinetics
across species.
One of the issues with NSAID-derived
such as 2 and 3 is that they have poor penetration of the central
nervous system.10,14 Thus, it is desirable to identify
-secretase
c-secretase modulators,
c
modulators with good CNS penetration (high brain-to-blood ratios,
Br:Bl). In order to assess the potential of compounds from this ser-
ies to access the CNS, compound 10h was dosed orally at 5 mg/kg
to mice and blood and brain samples were collected 2 h post-dose
(Table 5).
Thus compound 10h demonstrated good penetration of the CNS
and showed that a 5 mg/kg oral dose could deliver concentrations
in excess of 4
lM which is significantly higher than the in vitro IC50
(0.3 M) value indicating that compound 10h has the potential to
l
pound 10h had
concentrations (30 and 100
a
weak effect on cellular viability at high
M). However, no cytoxicity was ob-
deliver in vivo efficacy at low doses.
l
In summary, we have identified a potent and selective c-secre-
served with this compound at the concentrations at which it low-
ered Ab42.
tase modulator {(2S,4R)-1-{(1R)-4-methyl-1-[6-(trifluoromethyl)-
3-pyridinyl]pentyl}-2-[4-(trifluoromethyl)phenyl]-4-piperidinyl}-
acetic acid, 10h, which has good pharmacokinetic properties in the
mouse, rat and dog. Furthermore, this compound achieved good
brain exposure in the mouse and is thus suitable to explore the
Following in vitro potency assessment compounds with a pIC50
value P6 were assessed in terms of in vitro metabolic stability in
rat and human liver microsomes and for inhibition of five human
CYP isoforms (CYP1A2, 2C9, 2C19, 2D6 and 3A4). Selected ana-
logues were profiled to assess their potential as time-dependent
efficacy of
c-secretase modulator in this species. Data from
in vivo efficacy studies will be reported in due course.

A. Hall et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1306–1311
1309
Table 2
In vitro SAR for heterocyclic derivatives 10h and 11a–i
O
Na+
O
Ar
N
CF3
11a-i
Ab40 pIC50 (%inhibition)b
Notch pIC50 (%inhibition)b
a
a
a
Compd
Ar
Ab42 pIC50
1
3
n/a
n/a
7.4 0.13
5.4 0.26c
7.4 0.13
64.8 (32)
6.5 0.18
<4.7 (20)
d
N
10h
11a
11b
11c
11d
11e
11f
6.5 0.33
6.5 0.25
5.9 0.23
6.4 0.07
6.1 0.09
6.4 0.13
6.1 0.04
5.9 0.16
6.2 0.27
6.4 0.14
5.2 0.72
4.9 0.16
4.6 0.08
4.7 0.01
<4.7 (17)
4.7 0.21
<4.7 (22)
4.8 0.28
<4.7 (31)
4.9 0.09
<4.7 (24)e
4.9 0.06
<4.7 (17)
4.7 0.01
4.6 0.01
<4.7 (21)
<4.7 (27)
<4.7 (4)
F3C
N
N
F3C
F3C
F3C
N
N
N
N
N
F3C
F3C
N
N
N
N
N
11g
11h
11i
N
<4.7 (15)
5.4 0.78
N
N
CF3
a,b,c,d
See footnotes in Table 1.
Single experiment giving pIC50 excluded as max asymtote <40%.
e

1310
A. Hall et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1306–1311
Table 3
In vitro SAR for compounds 1, 3 and 4 and 10b–d, h and i showing that the piperidine derivatives are
c-secretase modulators
a
a
a
a
b
Compd
Ab42 pIC50
Ab40 pIC50
Ab38 pEC50
Abtotal pIC50
Cytotox pIC50
1
3
4
10b
10c
10d
10h
10i
6.9
5.8
5.7
6.0
6.0
6.0
6.0
6.0
6.7
<4.0
<4.0
<4.0
<4.0
4.4
6.9c
5.9
5.1
5.0
5.0
5.5
6.3
6.3
7.0
<4.0
<4.0
<4.0
<4.0
<4.0
4.0
<4.0
<4.0
<4.0
<4.0
<4.0
<4.0
4.0
4.4
4.6
4.0
<4.0
a
b
c
Values are single experiments.
WST-1 cytotoxicity assay.
Value is pIC50 as inhibitors cause a decrease in Ab38 production.
5. (a) Laudon, H.; Winbald, B.; Näslund, J. Physiol. Behav. 2007, 92, 115; (b) Zhang,
Y.; Xu, H. Curr. Mol. Med. 2007, 7, 687.
Table 4
In vivo DMPK for compounds 10h and 11d
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Farlow, M. R.; May, P. C. Clin. Pharmacol. 2007, 30, 317; (b) Siemers, E.; Skinner,
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Farlow, M. R.; Porsteinsson, A.; Tariot, P.; Zoulnouni, P.; Galvin, J. E.; Holtzman,
D. M.; Knopman, D. S.; Satterwhite, A.; Gonzales, C.; Dean, R. A.; May, P. C.
Neurology 2006, 66, 602; (d) Lanz, T. A.; Karmilowicz, M. J.; Wood, K. M.;
Pozdnyakov, N.; Du, P.; Piotrowski, M. A.; Brown, T. M.; Nolan, C. E.; Richter, K.
E. G.; Finley, J. E.; Fei, Q.; Ebbinghaus, C. F.; Chen, Y. L.; Spracklin, D. K.; Tate, B.;
Geoghegan, K. F.; Lau, L-F.; Auperin, D. D.; Achachter, J. B. J. Pharmacol. Exp.
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Engstrom, L.; Pinzon-Ortiz, M.; Fine, J. S.; Lee, H.-J. J.; zhang, L.; Higgins, G. A.;
Parker, E. M. J. Biol. Chem. 2004, 279, 12876; (b) Searfoss, G. H.; Jordan, W. H.;
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C.; Ryan, T. P. J. Biol. Chem. 2003, 278, 46107; (c) Hyde, L. A.; McHugh, N. A.;
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Zhang, L.; Parker, E. M.; Higgins, G. A. J. Pharmacol. Exp. Ther. 2006, 319, 1133;
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T. E.; Weggen, S.; Das, P.; McLendon, D. C.; Ozols, V. V.; Jessing, K. W.; Zavitz, K.
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Species
Moused
Parameter
10hb
11dc
CLb (mL/min/kg)
Vdss (L/kg)
t½ (h)
4
1
n.t.a
n.t.a
n.t.a
n.t.a
1.4 0.1
4.3 0.9
>100
g
Fpo (%)
Rate
Dogf
CLb (mL/min/kg)
Vdss (L/kg)
t½(h)
4
1
9
2
2.3 0.3
6.6 0.8
>100
3.0
3.0 0.3
95
1
Fpo (%)
4
CLb (mL/min/kg)
Vdss (L/kg)
t½ (h)
3
0.3
5.0
1.2
3.1
1.1 0.1
5.2 0.5
Fpo (%)
72
5
>100
a
b
c
nt = not tested.
Data are the mean from three animals for all species.
Data from rat studies are the mean from three animals, data from dog studies
are from a single animal.
d
Compound 10h dosed at 3 mg/kg (iv) and 10 mg/kg (po).
Compound 10h dosed at 1 mg/kg (iv) and 3 mg/kg (po), compound 11d dosed at
1 mg/kg (iv) and 2 mg/kg (po).
e
f
Both compounds dosed at 1 mg/kg (iv and po).
Oral bioavailability as sodium salt, vehicle = 1% methylcellulose.
g
Table 5
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Mouse CNS penetration data for compounds 10h
Compd
Blood concn (
l
M)
Brain concn (
4.199 1.021
lM)
Br:Bl
10ha
5.601 1.029
0.74 0.06
a
Compound dosed orally in (5 mg/kg) 1% (w/v) methylcellulose aq. Values are
the mean from three mice. Samples taken 2 h post-dose.
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Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.08.072.
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043064A1, 2006.
References and notes
1. Larson, E. B.; Kukull, W. A.; Katzman, R. L. Ann. Rev. Public Health 1992, 13, 431.
2. Hardy, J. Neuron 2006, 52, 3.
3. Parihar, M. S.; Hemnani, T. J. Clin. Neurosci. 2004, 11, 456.
16. Wilson, F.; Reid, A.; Reader, V.; Harrison, R. J.; Sunose, M.; Hernandez-Perni, R.;
Major, J.; Boussard, C.; Smelt, K.; Taylor, J.; Leformal, A.; Cansfield, A.;
Burckhardt, S. WO2006/045554A1, 2006.
17. Blurton, P.; Burkamp, F.; Churcher, I.; Harrison, T.; Neduvelil, J. WO2006/
008558A1, 2006.
18. See Supplementary data for full experimental details and characterising data.
The stereochemistry of the organozinc addition can be rationalised if the
addition proceeds via the sterically favoured (E)-iminium ion shown below,
4. (a) Dickson, D. W. J. Neuropathol. Exp. Neurol. 1997, 56, 321; (b) McKeith, I. G.;
Galasko, D.; Kosaka, K.; Perry, E. K.; Dickson, D. W.; Hansen, L. A.; Salmon, D. P.;
Lowe, J.; Mirra, S. S.; Byrne, E. J.; Lennox, G.; Quinn, N. P.; Edwardson, J. A.; Ince,
P. G.; Bergeron, C.; Burns, A.; Miller, B. L.; Lovestone, S.; Collerton, D.; Jansen, E.
N.; Ballard, C.; de Vos, R. A.; Wilcock, G. K.; Jellinger, K. A.; Perry, R. H. Neurology
1996, 47, 1113; (c) Mandal, P. K.; Pettegrew, J. W.; Masliah, E.; Hamilton, R. L.;
Mandal, R. Neurochem. Res. 2006, 31, 1153.

A. Hall et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1306–1311
1311
with attack from the least hindered Re-face. The (Z)-iminium ion is presumably
disfavoured due to the steric clash between the Ar group and the substituted
phenyl ring in the 2-position of the piperidine.
19. Hussain, I.; Hawkins, J.; Harrison, D.; Hille, C.; Wayne, G.; Cutler, L.; Buck, T.;
Walter, D.; Demont, E.; Howes, C.; Naylor, A.; Jeffrey, P.; Gonzalez, M. I.;
Dingwall, C.; Michel, A.; Redshaw, S.; Davis, J. B. J. Neurochem. 2007, 100, 802.
20. See Supplementary data for assay descriptions.
O
-
O
-
O
X
X
+
O
+
HN
Ar
ZnX
N
O
N
O
Ar
CF3
CF3
favoured
CF3
disfavoured
9
attack from
lower face
O
O
Ar
N
CF3
observed product