Discovery of BIIB042, a potent, selective, and orally bioavailable γ-secretase modulator

Article abstract of DOI:10.1021/ml200175q

We have investigated a novel series of acid-derived γ-secretase modulators as a potential treatment of Alzheimer's disease. Optimization based on cellular potency and brain pharmacodynamics after oral dosing led to the discovery of 10a (BIIB042). Compound 10a is a potent γ-secretase modulator, which lowered Aβ42, increased Aβ38, but had little to no effect on Aβ40 levels both in vitro and in vivo. In addition, compound 10a did not affect Notch signaling in our in vitro assessment. Compound 10a demonstrated excellent pharmacokinetic parameters in multiple species. Oral administration of 10a significantly reduced brain Aβ42 levels in CF-1 mice and Fischer rats, as well as plasma Aβ42 levels in cynomolgus monkeys. Compound 10a was selected as a candidate for preclinical safety evaluation.

Full text of DOI:10.1021/ml200175q

LETTER
pubs.acs.org/acsmedchemlett
Discovery of BIIB042, a Potent, Selective, and Orally Bioavailable
γ-Secretase Modulator
Hairuo Peng,*,† Tina Talreja,† Zhili Xin,† J. Hernan Cuervo,† Gnanasambandam Kumaravel,*,†
Michael J. Humora,‡ Lin Xu,§ Ellen Rohde,§ Lawrence Gan,§ Mi-young Jung,||
Melanie N. Shackett,|| Sowmya Chollate,|| Anthone W. Dunah,|| Pamela A. Snodgrass-belt,||
H. Moore Arnold,|| Arthur G. Taveras,† Kenneth J. Rhodes,|| and Robert H. Scannevin||
Departments of †Medicinal Chemistry, ‡Chemical Process, §Drug Metabolism and Pharmacokinetics, and Neurology Research,
Biogen Idec Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, United States
S Supporting Information
b
ABSTRACT: We have investigated a novel series of acid-derived γ-secretase
modulators as a potential treatment of Alzheimer's disease. Optimization based on
cellular potency and brain pharmacodynamics after oral dosing led to the discovery
of 10a (BIIB042). Compound 10a is a potent γ-secretase modulator, which
lowered Aβ42, increased Aβ38, but had little to no effect on Aβ40 levels both in
vitro and in vivo. In addition, compound 10a did not affect Notch signaling in our in
vitro assessment. Compound 10a demonstrated excellent pharmacokinetic para-
meters in multiple species. Oral administration of 10a significantly reduced brain
Aβ42 levels in CF-1 mice and Fischer rats, as well as plasma Aβ42 levels in
cynomolgus monkeys. Compound 10a was selected as a candidate for preclinical
safety evaluation.
KEYWORDS: Secretase, GSM, Alzheimer's, amyloid, Mannich reaction
lzheimer's disease (AD) is a devastating neurodegenerative
disorder for which there is no disease-modifying therapy
Tarenflurbil (1, EC50 = 300 μM, Figure 1)12 was progressed
through phase III clinical trials for AD but failed to achieve
efficacy, potentially due to weak GSM activity and poor brain
A
currently available.1 Multiple lines of evidence suggest that
amyloid-β (Aβ) peptide plays a pivotal role in the pathogenesis
of AD. Preventing the accumulation and aggregation of Aβ
peptide has been one of the major strategies in developing
disease-modifying AD therapies.2À4 Aβ peptides are produced
from sequential cleavage of amyloid precursor protein (APP) by
β-secretase and γ-secretase in the brain.5 Cleavage by γ-secretase
produces Aβ peptides that generally range from 37 to 42 amino
acids in length. Aβ42 is more amyloidogenic as compared to the
shorter Aβ isoforms and may serve as a key seed in the formation
of senile plaques and may be at least partially responsible for
mediating cognitive impairment in AD.6À8 γ-Secretase modula-
tors (GSMs) preferentially shift the carboxy-terminal cleavage
pattern on the β-secretase-processed APP (C99) to bias produc-
tion away from longer isoforms such as Aβ42 in favor of shorter,
less toxic Aβ isoforms, such as Aβ38. Because GSMs do not
inhibit the enzymatic activity of γ-secretase, they are much less
likely to interfere with processing and subsequent signaling
activities of other important substrates, such as Notch, and could,
therefore, potentially provide a better safety profile as compared
to the γ-secretase inhibitors (GSIs).9,10
penetration. Chiesi has recently advanced CHF5074 (2, EC50
=
40 μM, Figure 1) into a phase II clinical trial. Cognitive benefits
and plaque load reduction in the brain were reported after chronic
treatment of Tg2576 transgenic mice with CHF5074.13 This
compound is about 7-fold more potent than Tarenflurbil and has
improved brain exposure after prolonged dosing. There has been
an intensive effort to further improve potency and brain exposure
as exemplified by Merck's recent publications on a series of
carboxylic acid-derived GSMs (e.g., 3, EC50 = 0.6 μM, Figure 1).14
Eisai's GSM (4, EC50 = 0.08 μM, Figure 1) represents a different
class of GSMs that contain an aryl imidazole moiety instead of the
carboxylic acid.15 Additional patent literature in this field has
been extensively reviewed recently.15
Our program aimed to identify potent GSMs with favorable
brain exposure. As shown in Figure2, our early lead 5 was designed
to test the idea if an amino nitrogen atom was tolerated when
introduced off the biaryl acetic acid scaffold that is similar to those
of NSAIDs. Compound 5 was active in APP CHO cellular assay
(EC50 = 1 μM). However, brain exposure was limited (0.6 μM,
4 h) in mice after 50 mg/kg oral dosing, even though the plasma
The first generation of GSMs originated from an epidemio-
logical analysis, which showed that certain nonsteroidal anti-inflam-
matory drugs (NSAIDS) lowered the risk of developing AD, and
the effect was independent of COX inhibition.11 NSAID-derived
Received: July 20, 2011
Accepted: August 5, 2011
Published: August 05, 2011
r
2011 American Chemical Society
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LETTER
Scheme 1. Synthesis of Compound 10aa
Figure 1. Structures of GSMs.
a (a) BnBr, K2CO3, acetonitrile, room temperature, 6 h, 87%. (b) LiHMDS,
THF, CH3I, À78 °C to room temperature, 76%. (c) Pd/C, H2, MeOH,
3 h, 87%. (d) 4-Fluorobenzaldehyde, 4-methylpiperidine, trifluoro toluene,
microwave, 120 °C, 1 h, 42%. (e) Tf2O, pyridine, CH2Cl2, 75%. (f)
4-(Trifluoromethyl)phenyl boronic acid, Pd(PPh3)4, 1,2-dimethox-
yethane/ethanol/saturated Na2CO3, microwave, 120 °C, 0.5 h, 67%. (g)
NaOH, MeOH/THF (1:1), microwave, 100 °C, 10 min, 86%. (h) SCF
chiral separation, Chiralpak AD-H (2 cm  15 cm), 10% isopropanol
(0.1% DEA)/CO2, 100 bar, 60 mL/min, 220 nm.
Figure 2. Structures of early lead 5 and BIIB042.
demonstrated improved cellular potency; however, it had much
lower brain exposure (1.0 μM, 4 h) as compared to 6 and did not
reduce brain Aβ42 when dosed at 50 mg/kg orally. Heterocyclic
moieties were not well tolerated at the R3 position as exemplified
by compound 9 (EC50 = 4.5 μM).
concentration was excellent (14.9 μM). We then decided to
constrain the side chain into a more rigid structure and incorpo-
rate a basic nitrogen atom, in an effort to improve brain
penetration. Mannich reaction on 3-hydroxyphenyl acetic acid
(35, Scheme 1) provided an interesting and facile route to
construct a compact framework and incorporate amines such
as piperidine. Multipoint optimization based on cellular potency
and brain pharmacodynamic (PD) response in wild type mice
after oral dosing lead to the discovery of the preclinical candidate
BIIB042 (10a). Herein, we describe the syntheses, structureÀ
activity relationships (SARs), and profiles of this novel series of
carboxylic acid-derived GSMs.
Tables 1À3 summarize the SAR at various positions of the
molecule. CHO cells overexpressing the APP V717F mutation
were used to measure the effect of GSM compounds on Aβ
peptide (Aβ42, Aβ40, and Aβ38) production using a multiplex
Aβ ELISA assay to detect all isoforms simultaneously in a single
well. In our investigation, compounds that lowered the levels of
Aβ42 concomitantly elevated the levels of Aβ38, while leaving
Aβ40 levels generally unchanged. The PD response of these
compounds was measured in wild-type mice following oral
administration. Animals were sacrificed 4 h after dosing, and
brain and plasma samples were collected for analyses of both
drug exposure and Aβ levels.
As shown in Table 1, with a much more rigid and compact
structure and a basic amine as compared to the early lead 5,
compound 6 maintained moderate potency (EC50 = 1.1 μM) for
lowering Aβ42 in the APP CHO cellular assay. This was
accompanied by a 10-fold improvement in brain exposure
(brain concn = 7.4 μM, 4 h, po, 50 mg/kg) and a detectable
PD response (20% Aβ42 reduction). At the R3 position, 4-CF3
phenyl was found to be optimal. As exemplified in Table 1,
compound 7 (p-F-phenyl, EC50 = 2.3 μM) was less potent as
compared to 6. Compound 8 (4-t-butyl phenyl, EC50 = 0.56 μM)
Compounds 10À19 highlight the SAR at the R1/R2 position.
Substitution at this position appeared to greatly improve cellular
potency. As compared to compound 11, a simple methyl
substitution at the R1/R2 position improved the cellular potency
by 8-fold (Table 1, compound 10, EC50 = 0.39 μM). There was a
trend that bulkier groups at the R1/R2 position provided more
potent cellular activity as demonstrated by compounds 12, 13,
and 15À17, with compound 17 achieving 40 nM EC50 in the
APP CHO cellular assay. However, brain penetration tended to
diminish as the number of rotatable bonds increased and the
molecular weight passed 500. For example, compound 14
(EC50 = 0.12 μM) only achieved 30% Aβ42 reduction and
5.7 μM drug concentration in the brain when dosed at 50 mg/kg,
while the methyl analogue 10 resulted in 45% Aβ42 lowering and
18.4 μM drug concentration in the brain when dosed at
30 mg/kg. Compounds 18 and 19 have an advantage of
simplifying the stereochemistry. Unfortunately, the cyclopropyl
analogue 19 was weaker in lowering Aβ42 in the cell-based assay
(EC50 = 2.2 μM). The gem dimethyl analogue (18) showed
reasonable cellular potency (EC50 = 0.45 μM), however, had
only moderate brain PD response (30% Aβ42 reduction) in mice
at 30 mg/kg and did not show PD response in the brain after oral
dosing at 30 mg/kg in rat (data not shown).
The key SAR at the R5 position is highlighted by compounds
20À24. Various substitution patterns on the phenyl were
explored; 4-F phenyl appeared to be the best as in compound
10. For reasons not clear to us, compound 20 did not achieve a
PD response in the brain even though the cellular potency was
better, and the brain exposure was significant. A heterocyclic
moiety appeared to be not as well tolerated at the R5 position, as
exemplified by compound 23. The best heterocyclic analogue
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Table 1. SAR at the R1/R2, R3, and R5 Positions
a EC50 values were calculated as an average of at least two determinations. b PD responses were measure at 4 h after oral administration of compounds in a
solution formulation (ethanol:propylene glycol:10% solutol = 1:1:8). c Oral dosing at 50 mg/kg. d Oral dosing at 30 mg/kg. e NS, not significant. f NT,
not tested.
(24, EC50 = 0.58 μM) in our collection achieved favorable brain
exposure (brain concn = 10.9 μM), likely benefiting from a
4-CF3 substituted pyridyl group at the R5 position. However, the
PD response of 24 was rather moderate (23% Aβ42 reduction,
30 mg/kg).
moiety at this position led to much weaker cellular activity.
However, hydrophobic substitution on the piperidine was ben-
eficial in improving cellular potency. For example, the 4-CF3
substitution on piperidine rendered compound 26 2-fold more
potent in the cell-based assay (EC50 = 0.18 μM) as compared to
compound 10. Interestingly, the improved in vitro potency did
not translate into a better PD response in the brain despite
We then fixed R1/R2, R3, and R5 and explored the R4
position. As shown for compound 25 in Table 2, a piperazine
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Table 2. SAR at the R4 Position
Table 3. Separated Single Isomers of Compound 10
Aβ
Aβ42 red. brain brain/plasma
hERG
compd 42 EC50 (μM) (10 mpk) (%) concn (μM) EC50 (μM)
10a
0.17
0.15
0.89
40
38
4.6/10
6.6/7.4
15
4.6
10b
10c/10d
NT
deprotection to give intermediate 36. Then, 4-fluorobenzalde-
hyde and 4-methylpiperidine were condensed with 36 in trifluoro
toluene via a three components Mannich reaction to afford
intermediate 37. Triflation of 37 followed by Suzuki coupling
with 4-(trifluoromethyl)phenyl boronic acid provided 39, which
was hydrolyzed to compound 10. Using supercritical fluid (SCF)
chiral method, racemate 10 was separated into two single isomers
(10a and 10b). The absolute configuration of 10a was unam-
biguously established as R,R by a single crystal X-ray structure
determination (Supporting Information). The other two isomers
(10c + 10d) were very difficult to separate and were tested as a
mixture in the assays.
As shown in Table 3, isomers 10a and 10b showed similar
cellular potency in lowering Aβ42 (EC50 = 0.17 and 0.15 μM,
respectively). The Aβ40 levels were unchanged, and Aβ38 levels
were increased (EC50 = 0.15 and 0.11 μM, respectively). The
mixture of the other two isomers was much less active (EC50
=
0.89 μM) and was not profiled further at the time. Both 10a and
10b demonstrated a very good PD response in the brain in wild-
type mice after oral administration at 10 mg/kg. At 4 h postdose,
these compounds achieved 4.6 and 6.6 μM brain concentrations,
respectively, resulting in a 40 and 38% reduction in brain Aβ42
levels, as compared to the vehicle control. When tested in the
FastPatch hERG assay, compound 10b had an EC50 of 4.6 μM,
while isomer 10a had an EC50 of 15 μM. Therefore, we
proceeded to profile 10a more thoroughly.
Compound 10a demonstrated excellent permeability in
the Caco 2 assay [Papp(A À B) = 43.8 Â 10À6 cm/s, p ratio
(B À A/A À B) = 0.8] and was not a substrate for efflux
transporters. It did not inhibit any of the five major human CYP
isoforms assayed (3A4, 2C9, 2C19, 2D6, and 1A2; IC50 > 35μM),
and there was no evidence for time-dependent inhibition of
human CYP3A4. The in vitro microsomal stability of 10a was
good [Qh%: 27 (mouse), 24 (rat), 41 (dog), 25 (dog), and 34%
(human)]. Compound 10a was highly protein-bound across
species in mouse, rat, dog, monkey, and human plasma (fu% < 0.1%).
The thermodynamic solubility was moderate and measured
20À30 μg/mL for a crystalline HCl salt. In addition to the low
risk hERG readout, compound 10a was negative in the AMES
mutagenicity assay.
In terms of selectivity, compound 10a inhibited COX1 or
COX2 very weakly (IC50 = 35 and 27 μM, respectively). Com-
pound 10a was tested in a cell-based assay in which the levels of
HES1 protein were measured. HES1 expression is dependent
upon an intact Notch signaling cascade and is mediated via
cleavage of the Notch intracellular domain from the nascent
transmembrane protein by γ-secretase.16 Compound 10a was
found to have no effect on HES-1 after 24 h of incubation of the
cell with 10 μM compound in this assay.
a EC50 values were calculated as an average of at least two determina-
tions. b PD responses were measure at 4 h after oral administration of
compounds at 30 mg/kg in a solution formulation (ethanol:propylene
glycol:10% solutol = 1:1:8).
comparable brain exposures (Table 2). In the absence of a methyl
substitution on the piperidine, compound 27 was about 4-fold
less potent as compared to 10 in the cell-based assay. 4-Fluoro
substitutions, as in 28 (EC50 = 2 μM), was not beneficial. The
pyrrolidine analogue 29 was also weaker in the cell-based assay
(EC50 = 2.3 μM). Compound 31 exhibited better cellular
potency (EC50 = 0.17 μM); however, the brain exposure was
much lower (2.5 μM), resulting in a weak PD response. As
exemplified by compounds 32À34, spiro, bridged, and fused
cyclic amines were well tolerated at the R4 position. The PD
responses for these compounds weremoderate (Table 2). Overall,
compound 10 provided the most robust PD response in
the brain.
Compound 10a demonstrated very good pharmacokinetic
characteristics. As summarized in Table 4, it achieved good oral
bioavailability (44À106%) after a single oral dose at 10 mg/kg
(crystalline HCl salt formulated in suspension) in rats, dogs, and
The synthetic route to 10a is outlined in Scheme 1. The
R-methyl group was installed by benzyl protection of methyl
2-(3-hydroxyphenyl)acetate (35) followed by methylation and
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Table 4. Single Dose Pharmacokinetic Parameters of 10a in Rats, Dogs, and Cynomolgus Monkeysa
species
rat
route
dose (mg/kg)
Clp (mL/min/kg)
Vss (L/kg)
t1/2 (h)
AUC0À24 h (μg/mL h)
Cmax (μg/mL)
Tmax (h)
F (%)
ivb
poc
ivb
poc
ivb
poc
1
10
1
1.5 ( 0.1
0.8 ( 0.2
7.2 ( 1.7
6.6 ( 0.6
1.3 ( 0.2
2.3 ( 0.2
11.2 ( 4.3
25 ( 6
10.4 ( 0.8
49.7 ( 8.8
1.2 ( 0.1
5.2 ( 1.8
4.7 ( 1.4
48 ( 14
6.0 ( 0.4
1.4 ( 0.5
5.9 ( 2.3
1.7 ( 0.6
1.3 ( 0.6
2.0 ( 1.7
47 ( 9
44 ( 16
106 ( 33
dog
14 ( 1
0.9 ( 0.1
1.7 ( 0.3
10
1
monkey
3.7 ( 1.2
10
a Mean ( SD (n = 3). b Formulation iv EtOH:PEG400:water (10:40:50), 1 mL/kg. c Formulation po, 0.5% CMC, 0.2% Tween80, 5 mL/kg.
cynomolgus monkeys. Compound 10a had low clearance in rats
and cynomolgus monkeys with a t1/2 of 6 and 11 h, respectively.
In dogs, the clearance was higher, and the t1/2 was approxi-
mately 2 h.
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In conclusion, we have designed a novel series of acid-based
GSMs that are potent and have excellent brain exposure. On the
basis of its potent lowering of brain Aβ, its lack of Notch activity,
and its favorable pharmaceutical profiles, BIIB042 (10a) was
selected as a candidate for preclinical safety evaluation.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details for Aβ
b
and Notch assays, synthetic procedures, and analytical data for
compounds 6À34 and crystallographic data for compound 10a.
This material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Tel: 617-686-9487. Fax: 617-679-3635. E-mail: hairuo.peng@
biogenidec.com (H.P.) or gnanasambandam.kumaravel@
biogenidec.com (G.K.).
’ ACKNOWLEDGMENT
Wethank Drs. Alphonse Galdes, Wen-CherngLee, and William
Harris for their strong support of the program, Harriet Rivera for
compound management, DMPK group for the support on
compound profiling and PK studies, and neuropharmacology
group for the support on the in vivo studies.
’ REFERENCES
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