Discovery of SCH 900229, a potent presenilin 1 selective γ-secretase inhibitor for the treatment of Alzheimer's disease

Article abstract of DOI:10.1021/ml300044f

An exploration of the SAR of the side chain of a novel tricyclic series of γ-secretase inhibitors led to the identification of compound (-)-16 (SCH 900229), which is a potent and PS1 selective inhibitor of γ-secretase (Aβ40 IC₅₀ = 1.3 nM). Compound (-)-16 demonstrated excellent lowering of Aβ after oral administration in preclinical animal models and was advanced to human clinical trials for further development as a therapeutic agent for the treatment of Alzheimer's disease.

Full text of DOI:10.1021/ml300044f

Letter
pubs.acs.org/acsmedchemlett
Discovery of SCH 900229, a Potent Presenilin 1 Selective γ-Secretase
Inhibitor for the Treatment of Alzheimer’s Disease
Wen-Lian Wu,*,† Martin Domalski,† Duane A. Burnett,† Hubert Josien,† Thomas Bara,†
Murali Rajagopalan,† Ruo Xu,† John Clader,† William J. Greenlee,† Andrew Brunskill,∥ Lynn A. Hyde,‡
Robert A. Del Vecchio,‡ Mary E. Cohen-Williams,‡ Lixin Song,‡ Julie Lee,‡ Giuseppe Terracina,‡
Qi Zhang,‡ Amin Nomeir,§ Eric M. Parker,‡ and Lili Zhang‡
∥
†Department of Medicinal Chemistry, ‡Department of Neuroscience, Department of Pharmaceutical Sciences, and §Department of
Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033,
United States
S
* Supporting Information
ABSTRACT: An exploration of the SAR of the side chain of a novel tricyclic series of γ-secretase
inhibitors led to the identification of compound (−)-16 (SCH 900229), which is a potent and PS1
selective inhibitor of γ-secretase (Aβ40 IC50 = 1.3 nM). Compound (−)-16 demonstrated excellent
lowering of Aβ after oral administration in preclinical animal models and was advanced to human clinical
trials for further development as a therapeutic agent for the treatment of Alzheimer’s disease.
KEYWORDS: γ-Secretase inhibitor, Alzheimer’s disease, amyloid, notch, clinical candidate
lzheimer’s disease (AD) was first described a century ago1
A
and has since become increasingly prevalent in recent
decades, presumably reflecting an aging population. Current
standard treatments, chiefly cholinesterase inhibitors, are only
palliative in nature and are insufficient to stop the progression
of the disease.2 Alzheimer’s disease is a neurodegenerative
disorder manifested by cognitive and memory deterioration, as
well as impairment of language and other activities of daily life.
Two pathological hallmarks are intracellular neurofibrillary
tangles and extracellular amyloid plaques. The well-known
amyloid hypothesis postulates that production and deposition
of β-amyloid (Aβ) is the leading cause of damage and death of
neurons and eventual onset of Alzheimer’s disease.3,4 Aβ is
generated from the large transmembrane amyloid precursor
protein (APP) by two proteolytic reactions. Following cleavage
by β-secretase (BACE1) at the N-terminus, γ-secretase
processes the C-terminus to produce Aβ fragments of 37−42
residues. Aβ40 is the major isoform; however, Aβ42 is more
hydrophobic and thereby more prone to aggregate to form
plaques.5 In recent years, there has been much interest in
developing γ-secretase inhibitors as disease-modifying treat-
ments to slow the formation of amyloid and in theory have a
positive impact on Alzheimer’s disease, as reflected by reports that
several structurally distinct inhibitors, such as 1 (Semagacestat),6 2
(Begacestat),7 and 3 (Avagacestat)8 have progressed into different
stages of clinical trials (Figure 1).
Figure 1. Representative γ-secretase inhibitors.
mechanism-based side effects. In addition to APP, γ-secretase
also processes many other natural substrates, with the most
physiologically significant being the cell surface Notch receptor.
Notch processing is involved in cell differentiation and
development, and blocking the Notch pathway may have
detrimental side effects.9,10 A critical goal of this work was to
achieve potent γ-secretase inhibition with high selectivity
against Notch processing. A series of γ-secretase inhibitors
bearing novel tricyclic cores, developed in our laboratories, has
been previously reported.11,12 In this communication, further
structure−activity relationship (SAR) exploration of the side
Special Issue: Alzheimer’s Disease
Received: February 21, 2012
Accepted: April 9, 2012
Published: April 9, 2012
One critical aspect of development of γ-secretase inhibitors
for the treatment of Alzheimer’s disease is the potential for
© 2012 American Chemical Society
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ACS Medicinal Chemistry Letters
Letter
chain of the bispyran series and identification of a clinical
candidate will be described.
Scheme 2. Elaboration of 8b to Various Side Chain
Analogues
a
To facilitate synthesis of analogues bearing the bispyran core,
we designed and developed an efficient route to the allyl
substituted intermediate 8b starting from the readily available
racemic alcohol 4,11 as depicted in Scheme 1. Dess−Martin
a
Scheme 1. Synthesis of Tricyclic Intermediate 8b
a
Reagents and conditions: (a) O3, dichloromethane; Ph3P, NaBH4;
(b) 4-nitrophenylchloroformate; MeNH2; (c) ethyl isocynate;
(d) TsCl, Et3N; (e) NaCN, DMF; (f) i-PrSH, KOH, EtOH, 70 °C;
(g) mCPBA, CH2Cl2.
Scheme 3, the racemic alcohol 9 was first resolved by chiral HPLC
to give two pure enantiomers (+)-9 and (−)-9. The enantiomer
(−)-9 was more potent in Aβ40 inhibition than enantiomer (+)-9,
as listed in Table 1. Assignment of absolute configuration to the
enantiomer (−)-9 was based on the close similarity of related active
γ-secretase inhibitors and later confirmed by determining the X-ray
structure of its derivative sulfone (−)-16.19 As described above,
enantiomer (−)-9 was converted to its tosylate (−)-12, which was
treated with isopropyl mercaptan followed by oxidation of the
resultant sulfide to provide the sulfone (−)-14. The corresponding
ethyl sulfone analogue (−)-15 was also prepared accordingly. The
methyl sulfone (−)-16 was obtained by treatment of the tosylate
(−)-12 with n-tetrabutylammonium iodide and sodium meth-
ansulfinate in one-pot, although a small amount (5−10%) of the
O-alkylation product 17 was also isolated.20
As shown in Table 1, all three enantiomerically pure sulfone
analogues (−)-14, (−)-15, and (−)-16 were very potent in
reduction of Aβ40 and Aβ42, in both membrane and cell-based
assays. More importantly, all of them also lowered Aβ in vivo at
3 h following a single oral dose in transgenic CRND8 or
nontransgenic B6C3F1 mice.18 Particularly, the methyl sulfone
(−)-16 exhibited excellent Aβ lowering in vivo in both plasma
and cortex and was selected to be scaled up for further study.
In an effort to improve the overall yield of (−)-16, we
designed a tactic to take advantage of the seemingly wasted
diastereoisomer ( )-6a, as outlined in Scheme 4. Compound
6a was converted to the tricyclic compound 8a in three steps, as
described for compound 8b. The double bond of 8a was then
migrated using RhCl3·3H2O as a catalyst to give a mixture of
olefins 18, favoring the trans-isomer.21 Cleavage by ozonolysis
and reductive workup furnished the aldehyde 19. Conforma-
tional analysis revealed that the carboxyaldehyde group is
oriented axially, and also cis to the adjacent ring substituent.
We envisioned that, under basic conditions, this β-oriented
aldehyde would equilibrate to its more stable α-epimer
(equatorial orientation) that could be used for the synthesis
of the sulfone (−)-16. Indeed, treatment of 19 with potassium
carbonate in methanol at room temperature proceeded
smoothly to give the aldehyde 20,22 with complete inversion
a
Reagents and conditions: (a) Dess−Martin periodinane, CH2Cl2; (b)
(TMSOCH2)2, TMSOTf; (c) allyltrimethylsilane, BF3−OEt2, CH2Cl2;
(d) potassium peroxomonosulfate, MeCOMe−H2O; (e) MsCl, Et3N,
CH2Cl2; (f) t-BuOK, THF.
oxidation of the alcohol 4 gave an aldehyde13 which in turn was
converted to the acetal 5.14 Unlike the aldehyde intermediate,
which is prone to β-elimination under basic conditions, the
acetal 5 is very stable under basic and even mild acidic
conditions. Lewis acid catalyzed addition of allyltrimethylsilane
gave a mixture of two diastereoisomers 6a and 6b15 in a ratio of
approximately 1:2 that was separated by chromatography. The
desired isomer 6b was then oxidized to the sulfone 7b, whose
mesylate derivative was subsequently treated with potassium
tert-butoxide to effect a smooth ring closure, producing racemic
8b. With this tricyclic scaffold in hand, we next turned to
elaborate the allyl side chain to generate other polar functional
groups, as shown in Scheme 2.
The allyl compound ( )-8b was subjected to ozonolysis and
subsequent reductive workup to afford the racemic alcohol 9.
From this alcohol, several derivatives were prepared in
straightforward fashion. Treatment of 9 with 4-nitrophenylchlor-
oformate, followed by methylamine, gave carbamate 10; reaction
of compound 9 with ethyl isocyanate furnished carbamate 11.
Alternatively, the alcohol 9 was converted to its tosylate 12, which
was treated with sodium cyanide to give the nitrile 13. In another
avenue, compound 12 was reacted with isopropyl mercaptan to
generate a thioether intermediate that was oxidized with m-
chloroperbenzoic acid to afford the racemic sulfone 14.
As revealed in Table 1, analogues 10, 11, 13, and 14 were
potent in inhibiting Aβ40 production in the membrane and
cell-based assays,16,17 suggesting that a variety of structural
motifs are tolerated in this region. However, when compounds
13 and 14 were dosed orally in mice,18 only the sulfone 14
demonstrated lowering of Aβ in the cortex. Having achieved
preliminary success with an active series, we decided to
pursue enantiomerically pure analogues. Thus, as illustrated in
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ACS Medicinal Chemistry Letters
Letter
Table 1. In Vitro and in Vivo Biological Data
a,
b
a,
b
c
Aβ40 IC50 (nM)
membrane
Aβ42 IC50 (nM)
PS2/PS1
ratio
in vivo Aβ40 (%)
plasma
compd
R
cell
cell
cortex
(−)-9
(+)-9
OH
OH
20
320
8
18
ND
8
8
ND
6
ND
ND
3
( )-10
( )-11
( )-13
( )-14
(−)-14
(−)-15
(−)-16
(+)-16
OCONHMe
OCONHEt
CN
24
22
24
6
48
37
26
8
20
16
10
3
ND
6
d
d
e
+18
ND
d
SO2i-Pr
SO2i-Pr
SO2Et
6
−20
−57
−58
−79
−78
e
f
ND
26
−2
−60
−89
f
f
3
5
2
f
SO2Me
SO2Me
1.3
377
4
1
25
ND
ND
ND
a
b
c
The IC50 data are an average of at least two measurements; the standard deviation was 20%. Determined in HEKAwe‑Lon 293 cells. Measured at 3 h
d
e
after oral dosing, (−) indicates lowering, (+) indicates increase, see ref 18. These data are from CRND8 mice dosed at 30 mg/kg. These data are
from B6C3F1 mice dosed at 10 mg/kg. These data are from B6C3F1 mice dosed at 30 mg/kg.
f
a
Scheme 3. Synthesis of Enantiomerically Pure Sulfone
Analogues
Scheme 4. Alternative Route to Compound (−)-16
a
a
Reagents and conditions: (a) Potassium peroxomonosulfate,
MeCOMe−H2O; (b) MsCl, Et3N, CH2Cl2; (c) t-BuOK, THF; (d)
RhCl3−3H2O, EtOH, reflux; (e) O3, CH2Cl2, Ph3P; (f) K2CO3,
MeOH; (g) (EtO)2P(O)CH2SO2Me, LiHMDS, THF; (h) NaBH4,
THF−MeOH; (i) Chiralcel OD column.
a
Reagents and conditions: (a) Chiralcel OJ column, i-PrOH-hexanes;
(b) TsCl, Et3N, CH2Cl2; (c) RSH, KOH, EtOH, 70 °C; (d) mCPBA,
CH2Cl2; (e) n-Bu4NI, MeSO2Na, THF.
and optical rotation, is in full agreement with that of (−)-16
prepared according to Scheme 3.
at the α-position. Horner−Wittig elongation of the aldehyde 20
with diethyl methylsulfonomethylphosphanate under basic
conditions gave a mixture of α,β-unsaturated sulfones 21, in
favor of the trans-isomer.23 Reduction of 21 with sodium
borohydride furnished the racemic sulfone 16,24 which was
resolved on a Chiralcel OD column to obtain the desired
enantiomerically pure sulfone (−)-16 and its enantiomer
(+)-16. Not surprisingly, (+)-16 is much less potent than
(−)-16, as shown in Table 1. The spectroscopic character-
ization of enantiomer (−)-16, including proton NMR, LC-MS,
The success of the synthetic route described in Scheme 4 not
only augmented the overall yield of (−)-16 from 4% to 6% but
suggested immediately a unified pathway to (−)-16. As
depicted in Scheme 5, starting from the acetal intermediate 5,
oxidation with mCPBA gave the sulfone 22. Ring-opening of
the ketal was carried out using cyanotrimethylsilane instead of
allyltrimethylsilane,25 to give a mixture of two diastereoisomeric
alcohols 23 in a ratio of roughly 1:1. Without separation, the
alcohols were transformed to their mesylates, and base-promoted
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ACS Medicinal Chemistry Letters
Letter
a
GSI’s, such as semagacestat (PS2/PS1 = 1) and Begacestat
(PS2/PS1 = 1), and it may contribute to its high therapeutic
window observed in rodents. Moreover, compound (−)-16 was
found to be excellent at lowering of Aβ40 in all three
compartments (plasma, CSF, and cortex) in rats (ED50 values
of 1.1, 3.7, and 0.3 mg/kg, respectively) and dogs, and detailed
data will be reported in due course. As shown in Table 2, the
pharmacokinetic properties of (−)-16 were determined in rat,
monkey, and dog. Overall, it displayed good to excellent
exposure with sufficient oral bioavailability in all species tested.
In summary, we have identified and developed a series of
tricyclic analogues bearing two sulfone groups as potent and
selective γ-secretase inhibitors. Among them, sulfone (−)-16
exhibited significant selectivity against Notch processing and
demonstrated robust lowering of Aβ after oral administration in
rodents and large animals, as well as generally favorable
pharmacokinetic profiles across species. On the basis of these
promising results, (−)-16 was advanced to human clinical trials
for the treatment of AD.
Scheme 5. Efficient Synthesis of Compound (−)-16
a
Reagents and conditions: (a) mCPBA, CH2Cl2; (b) Me3SiCN, BF3−
OEt2; (c) MsCl, Et3N, CH2Cl2; (d) t-BuOK, THF; (e) DIBAL in
toluene, CH2Cl2; t-BuOK, THF.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details for synthetic procedures and compound
characterization for compounds 5−24 and crystallographic data
of compound (−)-16. This material is available free of charge
via the Internet at http://pubs.acs.org.
ring closure gave the tricyclic nitriles 24a and 24b, with the
ratio of α- to β-epimer being enriched to ca. 8:1. DIBAL
reduction of 24b gave the desired α-epimer aldehyde 20.
Conversion of the aldehyde 20 to (−)-16 was then achieved as
described previously in Scheme 3. Alternatively, similar
reduction of a mixture of 24a and 24b (1:4) followed by
treatment of the crude aldehyde with t-BuOK also furnished
20 as the major isomer (95% purity), which was used directly in
the next step. This streamlined synthesis of (−)-16 delivered a
higher overall yield (12%) than the combined yield from the
routes shown in Schemes 3 and 4. It also featured two other
advantages: no tedious separation of diastereoisomers 6a and
6b and no process-unfriendly ozonolysis operation.
Compound (−)-16 was characterized in different preclinical
species for its ability to reduce Aβ. When CRND8 mice were
acutely dosed orally with (−)-16, Aβ40 in plasma and cortex
were reduced significantly at the 3 h time point,18 with ED50
values of 0.5 and 0.4 mg/kg, respectively. In a separate
subchronic study, CRND8 mice were dosed with (−)-16 BID
orally for 6 days, and a similar lowering of Aβ in both plasma
(ED50 0.4 mg/kg) and cortex (ED50 0.3 mg/kg) was observed.
No evidence of Notch-related effects, such as a reduction in
thymus size or intestinal goblet cell hyperplasia, was observed.
Compound (−)-16 showed an IC50 of 46 nM in an in vitro cell-
based Notch cleavage assay.17 This level of selectivity between
Notch and Aβ40 processing was comparable to that of
semagacestat. Compound (−)-16 displayed a high PS2/PS1
ratio of 25 (see Table 1) when tested with reconstituted
γ-secretase complexes, suggesting it is a PS1 selective inhibitor of
γ-secretase.26 This feature is distinct from those of many early
AUTHOR INFORMATION
■
Corresponding Author
*Phone: 732-594-2987. Fax: 732-594-3007. E-mail: wen-lian.
wu@merck.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors would like to thank Drs. John Hunter, John
Piwinski, and Catherine Strader for their support. We gratefully
acknowledge Lisa Broske and her group for animal dosing and
Sam Wainhaus and his group for the pharmacokinetic sample
analysis. We thank Dr. Birendra Pramanik and his group and
Dr. Tse-Ming Chan and his group for analytical support, and
Drs. Jesse Wong, Dr. Xian Liang, and Mr. Yan Jin for scale-up
of some key intermediates.
ABBREVIATIONS
■
AD, Alzheimer’s disease; Aβ, β-amyloid; CSF, cerebrospinal
fluid; PS1, presenilin-1; PS2, presenilin-2; APP, amyloid
precursor protein; BACE1, β-secretase 1, β-site APP cleaving
enzyme; GSI, γ-secretase inhibitor; BID, twice daily; SAR,
structure−activity relationship; mCPBA, m-chloroperbenzoic
acid
ab
,
Table 2. Pharmacokinetic Profiles of Compound (−)-16
species (vehicle)
dose (mg/kg)
AUC (0−∞) (μM·h)
Cmax (μM)
Tmax (h)
T1/2 (h)
F (%)
CL (mL/min/kg)
Vd(ss) (L/kg)
rat (20% HPβCD)
rat (0.4% HPMC)
monkey (0.4% HPMC)
dog (0.4% HPMC)
10
10
5
1.4
1.0
0.65
0.24
1.39
2.74
0.7
0.3
1.7
2.0
1.1
1.0
29
6.4
45
86
69
5.4
3.4
1.9
3.1
20.8
8.2
1.7
8.9
4.6
5
85.6
23.9
a
b
Data are averages from three rats, monkeys, and dogs (n = 3; PO). CL and Vd(ss) obtained with iv administration (5 mg/kg for rat, 2.5 mg/kg
each for monkey and dog).
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(17) Sun, Z.-Y.; Asberom, T.; Bara, T.; Bennett, C.; Burnett, D.; Chu,
I.; Clader, J.; Cohen-Williams, M.; Cole, D.; Czarniecki, M.; Durkin, J.;
Gallo, G.; Greenlee, W.; Josien, H.; Huang, X. H.; Hyde, L.; Jones, N.;
Kazakevich, I.; Li, H. M.; Liu, X. X.; Lee, J.; MacCoss, M.; McCracken,
T.; Nomeir, A.; Mazzola, R.; Palani, A.; Parker, E. M.; Pissarnitski, D.;
Qin, J.; Song, L. X.; Terracina, G.; Vicarel, M.; Voigt, J.; Xu, R.; Zhang,
L.; Zhang, Q.; Zhao, Z. Q.; Zhu, X. H.; Zhu, Z. N. Cyclic
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