Discovery of a potent pyrazolopyridine series of γ-secretase modulators

Article abstract of DOI:10.1021/ml2000438

The synthesis and structure-activity relationship of a novel series of pyrazolopyridines are reported. These compounds represent a new class of γ-secretase modulators that demonstrate good in vitro potency in inhibiting Aβ₄₂ production. Example

Full text of DOI:10.1021/ml2000438

LETTER
pubs.acs.org/acsmedchemlett
Discovery of a Potent Pyrazolopyridine Series of γ-Secretase
Modulators
Jun Qin,*,† Wei Zhou,† Xianhai Huang,*,† Pawan Dhondi,† Anandan Palani,† Robert Aslanian,†
Zhaoning Zhu,† William Greenlee,§ Mary Cohen-Williams,‡ Nicholas Jones,‡ Lynn Hyde,‡ and Lili Zhang‡
†Department of Medicinal Chemistry and ‡Neurodegenerative Diseases, Merck Research Laboratories, 2015 Galloping Hill Road,
Kenilworth, New Jersey 07033, United States
§Department of Medicinal Chemistry, Merck Research Laboratories, 126 East Lincoln Avenue, Rahway, New Jersey 07065,
United States
S Supporting Information
b
ABSTRACT: The synthesis and structureÀactivity relationship of a novel series of
pyrazolopyridines are reported. These compounds represent a new class of γ-secretase
modulators that demonstrate good in vitro potency in inhibiting Aβ42 production.
Examples with statistically significant in vivo efficacy in reducing the production of rat
cerebrospinal fluid Aβ42 were also identified.
KEYWORDS: Alzheimer's disease, γ-secretase modulator, amyloid-β peptide, Notch
espite enormous efforts to develop cures for Alzheimer's
disease (AD), there is no solution to this medical problem
Scheme 1. Design of Pyrazolopyridine Series as γ-Secretase
Modulators
D
yet.1À3 AD is characterized by neuronal loss, neurofibrillary
tangle (NFT) formation, and extracellular deposition of amy-
loid-β (Aβ) peptide plaques. Patients normally show symptoms
of cognitive impairment, as well as disturbance in language,
memory, movement, attention, and orientation. The Aβ peptides
have been hypothesized to be the pathological cause of this
disease. The Aβ peptides are generated from sequential cleavage
of the amyloid precursor protein (APP) by two key proteases,
β-secretase 1 (BACE1) and γ-secretase.4,5 γ-Secretase cleavage
is heterogeneous, resulting in Aβ peptides that range from 37 to
42 amino acids in length. Aβ42 is more hydrophobic than other
shorter Aβ peptides and is found in disproportionately high
amounts in Aβ plaques. Development of γ-secretase inhibitors
(GSIs) holds promise for the treatment of AD. Several classes of
GSIs have been reported to demonstrate efficacy in reducing
overall production of Aβ peptides in plasma, cerebrospinal fluid
(CSF), and brain.6À8 However, recent preclinical experiments
demonstrated that inhibition of γ-secretase results in mechan-
ism-based GI toxicity such as thymus atrophy and intestinal
goblet cell hyperplasia because γ-secretase has other substrates in
addition to APP such as Notch to process, and cleavage of Notch
by γ-secretase is important for cellular gene transcription.9,10
The recent clinical results of GSI candidate semagacestat showed
that it not only failed to slow disease progression but also
increased the incidence of skin cancer of patients in the treatment
group than the placebo group.11,12 The failure of semagacestat
again raised concerns about the efficacy and safety of GSIs.
γ-Secretase modulators (GSMs) selectively reduce the produc-
tion of Aβ42 while maintaining other normal functions of
γ-secretase, including Notch processing and signaling. GSMs
interact with γ-secretase at an allosteric site, inducing a con-
formational change in the protease and causing a shift of cleavage
specificity to preferentially produce shorter, more soluble Aβ-
peptides such as Aβ38 instead of the toxic Aβ42.13À18 As a result,
GSMs should not cause Notch-related side effects and could
potentially provide a better safety profile than GSIs. Different
classes of GSMs have been reported to demonstrate in vivo
efficacy, including nonsteroidal anti-inflammatory drugs (NSAIDs)
with carboxylic acid moiety,19À24 compounds with noncar-
boxylic acid scaffold,25À27 and Eisai compound E2012 currently
under clinical investigation, containing 1-(2-methoxyphenyl)-4-
methyl-1H-imidazole substructure, which is essential part of Eisai
compound to maintain the GSM activity.28À31
We recently reported the discovery of a tetrahydro-pyrazolo-
pyridine series of γ-secretase modulators.32 An example from this
series demonstrated good in vitro potency but only moderate
in vivo efficacy in reducing rat CSF Aβ42. This molecule exhibited
Received: February 14, 2011
Accepted: March 23, 2011
Published: March 29, 2011
r
2011 American Chemical Society
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Table 1. Cell Aβ42 IC50, γ-Secretase Modulator Selectivity, in Vivo Efficacy, and PK Profile of Compounds 1À6
a IC50 values are reported as an average of multiple determinations (n g 2). b The ratio represents a measure of GSM selectivity and the ability to reduce
the Aβ42 without affecting the total Aβ production. c n.s.e., no statistically significant efficacy.
Table 2. Cell Aβ42 IC50, γ-Secretase Modulator Selectivity, in Vivo Efficacy, and PK Profile of Compounds 7À14
a IC50 values are reported as an average of multiple determinations (n g 2). b The ratio represents a measure of GSM selectivity and the ability to reduce
the Aβ42 without affecting the total Aβ production. c n.s.e., no statistically significant efficacy. d n.a., not available.
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Table 3. Cell Aβ42 IC50, γ-Secretase Modulator Selectivity, in Vivo Efficacy, and PK Profile of Compounds 15À22
a IC50 values are reported as an average of multiple determinations (n g 2). b The ratio represents a measure of GSM selectivity and the ability to reduce
the Aβ42 without affecting the total Aβ production. c n.s.e., no statistically significant efficacy.
a relatively high efflux ratio, which could be the cause for its
limited brain penetration and in vivo efficacy. We decided to
explore the pyrazolopyridine core, which might offer better
physicochemical properties and efficacy than the tetrahydro-
pyrazolopyridine series (Scheme 1). Herein, we discuss the
synthesis and structureÀactivity relationship (SAR) of this
scaffold as a different class of γ-secretase modulators.
The SAR of this pyrazolopyridine series was examined on the
R1 and R2 substituents. Initially, we varied R1 while maintaining
R2 as a hydrogen. A series of compounds (1À6) with a variety
of N-benzyl groups as R1 were prepared, and SAR data are
presented in Table 1. 4-Methoxybenzyl derivative 1 showed
moderate activity (Aβ42 IC50 = 168 nM).33 Replacement of the
methoxybenzyl group of 1 with a 1-(4-fluorophenyl)ethyl group
(2) maintained similar potency. After resolving this enantiomeric
mixture, the (S)-enantiomer 4 was 3-fold more potent than the
(R)-enantiomer3. Compound 5with a 1-(3,5-difluorophenyl)ethyl
group also demonstrated good activity similar to that of 4. When
the methyl substituent attached to benzylic carbon in 4 was
changed to an ethyl group (6), it slightly reduced the potency.
Compounds 4 and 5 were dosed orally in rats at 30 mg/kg, but
they did not demonstrate statistically significant efficacy in
reducing CSF Aβ42. The pharmacokinetics of 4 and 5 revealed
that they had limited brain exposures 3 h after dosing (4: brain
C3h = 0.17 μM; 5: brain C3h = 0.14 μM).34 Not surprisingly,
analogues 4 and 5 were found to be PGP efflux substrates (4:
Pa-b = 9 nm/s, Pb-a = 314 nm/s, and P ratio = 33.8; 5: Pa-b
=
85 nm/s, Pb-a = 324 nm/s, and P ratio = 3.85).
The SAR of R2 was conducted to further improve the in vitro
and in vivo activity, while maintaining R1 as a (S)-(1-(4-fluor-
ophenyl)ethyl group. We prepared a series of analogues (7À14),
for which key data are summarized in Table 2. A variety of
functionalities including electron deficient (7 and 9À11), elec-
tron rich (12), hydrophilic (13), and sterically hindered (14)
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Scheme 2. Synthesis of Compound 4a
a Reagents and conditions: Method 1: (a) NaH, 1-(1-bromoethyl)-4-fluorobenzene, THF/DMF, 59%. (b) i-PrMgCl LiCl, 3-methoxy-4-(4-methyl-1H-
3
imidazol-1-yl)benzaldehyde, THF, 48%. (c) DessÀMartin periodinane, CH2Cl2, 67%. (d) NH2NH2, Py, 60 °C, 39%. (e) POCl3, 71%. (f) Chiral HPLC
separation. Method 2: (a) (R)-1-(4-fluorophenyl)ethanol, PBu3, ADDP, THF, 0 f 80 °C, ∼50%. (bÀe) The same as method 1.
Scheme 3. Synthesis of Compounds 8À11 and 13a
a Reagents and conditions: (a) PBu3, ADDP, (R)-1-(4-fluorophenyl)ethanol, THF, 80 °C, 60%. (b) NaOH, H2O/MeOH, 95%. (c) Cyanuric fluoride,
Py, CH2Cl2. (d) NaBH4, CH2Cl2/MeOH, 81% for two steps. (e) PMBBr, NaH, THF, 81%. (f) i-PrMgCl LiCl, 3-methoxy-4-(4-methyl-1H-imidazol-
3
1-yl)benzaldehyde, THF, 76%. (g) DessÀMartin periodinane, CH2Cl2, 90%. (h) NH2NH2, EtOH, 80 °C. (i) POCl3, Py, 50 °C, 25% for two steps. (j)
CAN, CH3CN/H2O, 76%. (k) NH3/H2O, I2, 60 °C, 10%. (l) DAST, CH2Cl2, 15%. (m) PDC, CH2Cl2, 98%. (n) CH3MgBr, THF, 75%.
groups were well tolerated. Compounds with chloride, methyl, or
hydroxymethyl group as R2 (7, 12, and 13) showed very similar
activity to 4. Analogues bearing larger R2 substitution such as
difluoromethyl (9), difluoroethyl (10), and 4-methoxybenzyl
group (14) were slightly less active than 4. It was also the case for
compound 11 with a nitrile group as R2. One exception was when
R2 was a fluoromethyl group (8), which was 6-fold less potent
than 4. Compound 7 (R2 = Cl) was the most potent derivative
from this part of the study (Aβ42 IC50 = 70 nM). Analogues 7, 9,
10, and 12 were examined in our rat in vivo model, but only 7
demonstrated good efficacy in reducing CSF Aβ42 (À32% Aβ42,
3 h after 30 mg/kg oral dosing). Not surprisingly, compound 7
had good brain exposure (brain C3h = 0.92 μM), and it was not a
PGP efflux substrate, while compounds 9 and 10 had little to no
plasma and brain exposure. In the case of 12, this molecule was a
PGP efflux substrate (12: Pa-b = 48 nm/s, Pb-a = 412 nm/s, and P
ratio = 8.50). These SAR data demonstrated that a chloride
group was the optimal R2 substituent for obtaining rat in vivo
efficacy.
With chloride established as the best R2 substituent for in vivo
efficacy, we carried out additional SAR at R1 with the hope of
optimizing physicochemical properties such as lipophilicity and
brain penetration to positively impact in vivo activity. To this
end, a variety of fluorinated N-benzyl analogues were then
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synthesized and tested (Table 3). 3,4-Difluorophenyl and 2,
5-difluorophenyl derivatives (15 and 16) maintained activities
similar to that of 4-fluorophenyl analogue 7. Interestingly,
compound 17 with a 3,5-difluorophenyl group was 2-fold more
potent than 7 but lost its selectivity as a modulator. Additional
fluorination on the phenyl ring (18) did not help improve the in
vitro activity. Varying the side chain attached to the benzylic
carbon from a methyl (18) to an ethyl (19) group improved in
vitro potency 2-fold, but this was not the case for hydroxymethyl
(20), (methylsulfonyl)ethyl (21), or methylene groups (22).
Analogues 15, 16, and 18À20 were tested in our rat in vivo
model. Compounds 15, 16, and 19 were as efficacious as 7 in
reducing CSF Aβ42, while 18 was superior (À45% Aβ42, 3 h after
30 mg/kg oral dosing). These compounds demonstrated good
plasma and brain exposure. Compound 20 did suffer from poor
brain exposure (brain C3h = 0.10 μM). It should be noted that all
of the compounds tested in rat did not show efficacy to reduce
CSF Aβ40 and Aβtotal at the dosed level. These compounds did
not affect Notch cleavage at concentrations up to 20 μM. The
result was consistent with the finding in the Aβtotal assay. Notch
signaling, assessed by Hes-1 expression, was also not affected in
studies conducted in mouse and dog.
The synthesis of 4 is described in Scheme 2. In method 1,
alkylation of 23 with 1-(1-bromoethyl)-4-fluorobenzene pro-
vided 24. Coupling of 24 with 3-methoxy-4-(4-methyl-1H-
imidazol-1-yl)benzaldehyde afforded an alcohol intermediate,
which was then oxidized to give ketone 25. Compound 25 was
transformed into 4 by hydrazone formation and ring closure,
followed by chiral HPLC separation of enantiomers. Alternatively,
in method 2, a Mitsunobu reaction of 23 with (R)-1-(4-fluorophe-
nyl)ethanol installed the chirality of 4 atan early stage. Compounds
5, 6, 15, 16, and 18À22 werepreparedbymethod1.35 Analogues 7,
12, and 17 were synthesized by method 2.
Synthesis of compounds 8À11 and 13 are presented in
Scheme 3. A Mitsunobu reaction of 26 with (R)-1-(4-fluorophe-
nyl)ethanol provided chiral ester 27. This compound was
hydrolyzed under basic conditions to give an acid intermediate,
which was then activated by cyanuric fluoride and reduced by
NaBH4 to afford compound 28. PMB protection of 28, followed
by coupling with 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)-
benzaldehyde, gave an alcohol intermediate, which was then
converted to 14 by oxidation of this alcohol to a ketone,
hydrazone formation from this ketone, and ring closure using
POCl3. The PMB protecting group of compound 14 was
removed, and the resulting alcohol 13 was converted to com-
pound 8 by DAST treatment. Compounds 9À11 were prepared
by a similar method to that described for 8.
In summary, we discovered a series of pyrazolopyridines as
potent γ-secretase modulators that demonstrated good in vitro
activity for reducing Aβ42 production. Several analogues were
identified to show statistically significant in vivo efficacy, with
compound 18 providing the greatest reduction of CSF Aβ42 in
rats. This compound underwent additional testing, and the
results will be the subject of a future publication.
’ AUTHOR INFORMATION
Corresponding Author
*Tel: 908-740-3904. Fax: 908-740-7664. E-mail:jun.qin@merck.
com (J.Q.). Tel: 908-740-3487. E-mail:xianhai.huang@merck.
com (X.H.).
’ ACKNOWLEDGMENT
We thank Drs. Chad Bennett, Andrew Stamford, and Eric
Parker for proofreading and comments on the preparation of
manuscript.
’ ABBREVIATIONS
AD, Alzheimer's disease; NFT, neurofibrillary tangle; Aβ, amyloid-β;
BACE1, β-secretase 1, β-site APP cleaving enzyme 1; APP, amyloid
precursor protein; GSIs, γ-secretase inhibitors; GSMs, γ-secretase mod-
ulators; CSF, cerebrospinal fluid
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