Identification and Preclinical Evaluation of the Bicyclic Pyrimidine γ-Secretase Modulator BMS-932481

Article abstract of DOI:10.1021/acsmedchemlett.8b00541

A triazine hit identified from a screen of the BMS compound collection was optimized for potency, in vivo activity, and off-target profile to produce the bicyclic pyrimidine γ-secretase modulator BMS-932481. The compound showed robust reductions of Aβ

Full text of DOI:10.1021/acsmedchemlett.8b00541

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Letter
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Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
Identification and Preclinical Evaluation of the Bicyclic Pyrimidine
γ‑Secretase Modulator BMS-932481
Kenneth M. Boy,*,†,⧫ Jason M. Guernon,†,∥ Dmitry S. Zuev,†,⊥ Li Xu,†,§ Yunhui Zhang,†,∥
Jianliang Shi,†,∥ Lawrence R. Marcin,†,● Mendi A. Higgins,†,§ Yong-Jin Wu,†,⧫
Subramaniam Krishnananthan,†,∥ Jianqing Li,†,⧫ Ashok Trehan,† Daniel Smith,†,∥ Jeremy H. Toyn,†,¶
Jere E. Meredith,†,○ Catherine R. Burton,† S. Roy Kimura,†,■ Tatyana Zvyaga,†,§ Xiaoliang Zhuo,†,⧫
Kimberley A. Lentz,†,△ James E. Grace,†,⬡ Rex Denton,†,∥ John S. Morrison,†,∥ Arvind Mathur,‡
Charles F. Albright,†,⬢ Michael K. Ahlijanian,†,◊ Richard E. Olson,†,⧫ Lorin A. Thompson,†,□
and John E. Macor†,▼
†Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States
‡Bristol-Myers Squibb, Princeton, New Jersey 08543, United States
S
* Supporting Information
ABSTRACT: A triazine hit identified from a screen of the BMS compound collection was optimized for potency, in vivo
activity, and off-target profile to produce the bicyclic pyrimidine γ-secretase modulator BMS-932481. The compound showed
robust reductions of Aβ1−42 and Aβ1−40 in the plasma, brain, and cerebrospinal fluid of mice and rats. Consistent with the γ-
secretase modulator mechanism, increases in Aβ1−37 and Aβ1−38 were observed, with no change in the total amount of Aβ1−x
produced. No Notch-based toxicity was observed, and the overall preclinical profile of BMS-932481 supported its further
evaluation in human clinical trials.
KEYWORDS: Alzheimer’s disease, clinical candidate, gamma-secretase modulator, bicyclic pyrimidine
lzheimer’s disease (AD) is a neurodegenerative disorder
Aof the elderly. Progressively worsening symptoms include
memory loss, difficulty with language and abstract thinking,
difficulty with familiar tasks, and impaired recognition of family
and friends. Death occurs on average 10 years after initial
diagnosis. The prevalence of AD in the U.S. is ca. 5.7 million
people and is expected to grow significantly in the coming
decades.1 The pathology of AD precedes the onset of
symptoms by a decade or more and is characterized by the
deposition of amyloid plaques and neurofibrillary tangles in the
brain. The current standard of care, acetylcholinesterase
inhibitors and an NMDA antagonist, provides minimal and
temporary benefit, and does not prevent progression of the
disease. Much of AD drug discovery has focused on reducing
the production of the Aβ peptides, which produce the
characteristic amyloid plaques found in the brain. Inhibitors
of the enzymes responsible for Aβ production, beta- and
gamma-secretase (GS), have entered clinical trials but have
failed to achieve commercialization. Recently, several late-stage
trials of beta-secretase (BACE) inhibitors failed to achieve
clinical success. Merck has announced that the study of
verubecestat in prodromal AD patients was suspended
following an interim safety analysis that predicted an
inadequate benefit/risk ratio,2 and AstraZeneca/Lilly has
terminated the study of lanabecestat in AD patients with
either mild cognitive impairment or mild dementia3 because it
was unlikely to meet the primary end points of the trial.4
Likewise, despite the enormous effort expended to advance six
different gamma-secretase inhibitors (GSIs) into Phase II/III
clinical trials, these agents failed in part due to toxicity
stemming from suppressing the proteolysis of other GS
substrates, most notably Notch.5 An alternative drug
mechanism, gamma-secretase modulators (GSMs), seeks to
exploit the differing potential of the several endogenous Aβ1−x
peptide species to aggregate to form neurotoxic oligomers.
Specifically, GSMs shift the distribution of gamma secretase
cleavage products away from the longer Aβ1−42 and Aβ1−40
Received: November 9, 2018
Accepted: February 4, 2019
© XXXX American Chemical Society
A
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ACS Medicinal Chemistry Letters
Letter
peptides to the shorter forms Aβ1−38 and Aβ1−37.6 The shorter
species are less lipophilic, less aggregation-prone, and less
position of the aryl E-ring relative to the core. Second,
replacement of the 4-methylimidazole A-ring with 4-
chloroimidazole provided an improvement in both potency
and CYP3A4 inhibition profile. Together, these features
increased the potency of 3 vs 2 by an order of magnitude
(IC50 = 2.0 nM). Consistent with its high potency relative to 2,
compound 3 demonstrated an in vivo pharmacologic response
in multiple species. In LaFerla mice, a 30 mg/kg oral dose of 3
reduced the level of brain Aβ1−42 by 86% after 3 h, and in
Harlan Sprague−Dawley rats, a 10 mg/kg oral dose reduced
Aβ1−42 by 59% 3 h postdose. The corresponding plasma
concentrations were 2.1 μM in LaFerla mice and 1.7 μM in rat,
and the B/P ratio in rats was 0.38. Furthermore, the metabolic
profile of 3 was improved over 2, with 96% of parent
compound remaining after a 10 min incubation with human
liver microsomes,14 while in vitro biotransformation assays
showed that metabolism was confined to N-demethylation and
monohydroxylation of the D-ring. An AUC0−24h of 7.6 μM·h
elicited our targeted 25% AUC0−24h reduction15 of rat brain
Aβ1−42. Allometric scaling of the results from similar
experiments in dog and cynomolgus monkey predicted a
human dose for 25% lowering of Aβ1−42 of 90 mg QD (1.3
mg/kg), aided by the oral bioavailability across species (49%,
64%, and 44% in rat, dog, and cynomolgus monkey,
respectively).
neurotoxic than aggregates of Aβ1−42 and, in fact, may play a
7
direct role in hindering the aggregation of Aβ1−42
.
Importantly, toxicity arising from the suppression of the
Notch signaling pathway is avoided by the GSM mechanism
because GS activity is not inhibited. Thus, GSMs offer an
attractive alternative disease-modifying mechanism to avoid
GSI toxicity.
Efforts in our laboratories to discover a GSM began with a
screen8 of the BMS compound collection, which identified
triazine 1 (Figure 1). The IC50 for Aβ1−42 lowering was 120
Given the improvements in PK/PD relative to 2, we profiled
3 for safety. Patch-clamp electrophysiology revealed potent
inhibition of the hERG ion channel (IC50 = 200 nM).
However, the low free fraction of 3 (0.1%) contributed to a
satisfactory predicted safety margin with regard to hERG-
mediated cardiac events since the QRT elongation effects of
hERG inhibition are driven by the free-drug concentration.
This prediction was confirmed by a rabbit telemetry study,
which demonstrated a 40-fold safety margin vs the hERG
NOAEL of 15 μM. Compound 3 was then tested in rats for 4
days after oral dosing at 10, 30, and 100 mg/kg. Visibly yellow
plasma at all doses alerted us to an increase in unconjugated
bilirubin, and upon further investigation, significant inhibition
of hUGT1A1 (IC50 = 1.4 μM) and OATP1B1 (690 nM) was
found. Furthermore, detailed tissue examination from the same
study also revealed hepatocellular necrosis at all doses studied,
which precluded a viable path forward for this compound.
It is widely recognized that high lipophilicity is associated
with a greater chance of drug toxicity,16 and in light of the
profile of 3, we pursued a strategy of lowering cLogP. Reducing
lipophilicity in CNS drugs can be particularly challenging since
overly polar molecules generally fail to cross the blood−brain
barrier, and many CNS targets often prefer lipophilic
compounds.17 Thus, balancing potency and polarity for CNS
drugs in general, and GSMs in particular, is a well-recognized
challenge.18 After examining compounds from several sub-
series, we found that (S)-7-(4-fluorophenyl)-N2-(3-methoxy-4-
(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihy-
dro-5H-cyclopenta[d]pyrimidine-2,4-diamine (4, BMS-
932481) had the best balance of potency, efficacy, and off-
target profile (Table 1).
Figure 1. Novel triazine/pyrimidine γ-secretase modulators.
nM in our primary H4 cell-based assay.9 No effect was seen on
total Aβ1−x formation, whereas increased levels of Aβ1−37 and
Aβ1−38 were observed in experiments using urea gel Western
blotting (data not shown). Taken together, these results firmly
establish 1 as a GSM. The central triazine core (C ring, Figure
1), flanked by a triazolyl anisole biaryl moiety (A−B rings) and
an aromatic group (E ring), was topologically similar to other
GSMs known in the patent literature. However, both the Eisai
cinnamide10 and Schering−Plough alkenyl oxadiazole11
chemotypes possessed a methine linker between the B- and
C-rings, so the aniline NH linking the B and C rings in 1 was
unique in the public literature at that time.12 Additionally, the
triazine 4-NHMe substituent represented an additional vector
for potential optimization.
Compound 1 was rapidly modified to incorporate a 4-
methylimidazole A-ring and benzyl E-ring to form compound
2, which was potent (Aβ1−42 IC50 = 31 nM) in our primary
assay. Triple transgenic LaFerla mice,13 which exhibit
accelerated plaque and tangle pathology resulting from the
presence of the APP Swedish, MAPT P301L, and
PSEN1M146V mutations, were orally dosed at 30 mg/kg
with compound 2 in a solution formulation. At 3 h postdose, a
32% reduction in brain Aβ1−42 was observed, with a brain to
plasma concentration ratio (B/P) = 0.47. Compound 2
exhibited liabilities that would need to be addressed in
subsequent compounds, specifically a short half-life as a
consequence of ubiquitous metabolism, potent hERG
inhibition, and potent and time-dependent CYP3A4 inhibition.
After extensive structure−activity relationship exploration, we
identified and integrated two structural modifications leading
to pyrimidine 3. First, the change from a triazine to a
pyrimidine C-ring core permitted the fusion of an additional
carbocyclic ring (D-ring, Figure 1), which restricted the
Compound 4 differs from compound 3 primarily by
changing the A-ring to the more polar 3-methyl triazole,
which resulted in an increased free fraction (0.6%), consistent
with our strategy. The Aβ1−42 IC50 of 4 was 6.6 nM, slightly
less potent than 3, highlighting a trade-off between potency
and polarity. Importantly, and consistent with the GSM
mechanism, treatment of cultured H4-APPsw cells with 4
B
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Letter
Table 1. Key Parameters of Compounds 2, 3, and 4
Table 2. Detailed Profile for Compound 4 (BMS-932481)
2
3
4
assay
result
a
Aβ1−42 IC50 (nM); n = 12
Aβ1−40 IC50 (nM); n = 3
Aβx‑42 IC50 (nM); n ≥ 3
total Aβ1−x inhib. at 50 μM (%); n ≥ 3
AMES result
metabolic stability T1/2: human, rat, mouse,
cynomolgus monkey, dog (min)
plasma free fraction: human, rat, mouse,
cynomolgus monkey, dog (%)
6.6 2.3
IC50 Aβ1−42 (nM)
31
32
2.0
86
59
4.42
0.1
7.6
90
6.6
81
41
3.97
0.6
4.0
110
b
25
8
Aβ1−42 reduction in mice (%)
Aβ1−42 reduction in rats (%)
shake flask log D (pH 6.5)
human plasma free fraction
active AUC0−24 (μM·h)
c
5.5 3.6
30 10
negative
30, 28, 36, 11, 27
calcd human efficacious dose (mg QD)
0.6, 0.7, 0.7, 1.3, 0.8
a
b
n = 315, 68, and 12, respectively. Reduction in brain Aβ1−42
LaFerla mice, 30 mg/kg po, 3 h postdose, n = 3. Reduction in brain
Aβ1−42, Sprague−Dawley rat, 10 mg/kg po, 3 h postdose, n = 5.
,
c
CYP 450 HLM inhibition IC50 (μM) 1A2,
2B6, 2C8, 2C9, 2C19, 2D6, 3A4
CYP 3A4 HLM time-dependent inhib.
>40, > 40, 4.5, 7.4,
8.3, 18, 0.2
KI (μM)
Kinact (min
hERG IC50 (μM)
Caco-2 Papp, efflux ratio
PSA (Å2)
pKa, spectrophotometric
shake flask log D at pH 6.5, 7.4
melting point (°C)
aq. solubility at pH 1.0, 6.5 (μg/mL)
83
0.47
1.2
3.5, 0.8
90
2.0, 5.9
3.97, 4.34
230
resulted in a large decrease in Aβ1−42 and Aβ1−40 and a
corresponding increase in Aβ1−37 and Aβ1−38 (Figure 2) as
measured by mass spectrometry. Total Aβ1−x was unchanged at
concentrations of 4 up to 10 μM, as determined by Aβ1−x
ELISA. Furthermore, the same distribution among Aβ peptide
species was recapitulated in both rat brain and CSF after
intravenous administration of 4.19 The amount of Aβ1−42 in the
brains of wild-type mice was reduced by 81% 3 h after a 30
mg/kg oral dose. In rats dosed orally at 10 mg/kg, brain Aβ1−42
was reduced by 41% vs predose levels at the 5 h time point,
with a concentration of 1.4 μM in plasma and a B/P ratio of
0.23. Compound 4 showed low clearance in rat (11.2 mL/
min/kg), with a volume of distribution of 2.3 L/kg and a half-
life of 2.7 h (Table 2). In preclinical species, oral bioavailability
was 98%, 85%, and 45% in rat, dog, and cynomolgus monkey,
respectively, when dosed as a nanosuspension.20 Further
testing in rats enabled generation of a PK/PD relationship
fitted to an indirect response model.21 When integrating over a
24 h time period, a 3 mg/kg dose reduced brain Aβ1−42 AUC
by 45% with an exposure of 9.7 μM·h, and a 10 mg/kg dose
reduced brain Aβ1−42 AUC by 66% with an exposure of
32 μM·h. Using these data, we calculated that a plasma
exposure of 4.0 μM·h would achieve a 25% AUC reduction of
Aβ1−42. Human PK was predicted by allometric scaling of PK
results from rat, dog, and cynomolgus monkey. Combining the
predicted human PK with the rat PK/PD forecasted that a
total oral daily human dose of 110 mg (1.6 mg/kg) would
result in a 31% reduction in brain Aβ1−42 and that a 446 mg
total daily dose would result in a 57% reduction in brain
Aβ1−42. We observed a low peak-to-trough exposure profile,
resulting in a predicted Cmax at the two doses of 0.32 and 1.3
μM, respectively. The projected human exposure calculations
enabled interpretation of the metabolic profiling data.
−1
)
a
b
19, 0.1
c
iv PK parameters
species
d
e
e
rat
2.7 0.6
monkey
dog
t1/2 (h)
2.9 1.0
31.3 9.5
8.7 1.1
12.5 1.2
CL
11.2 0.4
(mL/mi-
n/kg)
Vss
2.3 0.4
5.4 0.8
45
6.1 0.3
85
(L/kg)
F (%)
f
98
g
projected human PK parameters
dose (mg QD)
110, 446
0.32, 1.30
4.0, 16.2
31, 57
c
Cmax (μM)
AUC (μM·h)
Aβ1−42 reduction (%)
a
b
Octanol/water partitioning. Crystalline material. Sprague−Dawley
rat, male cynomolgus monkey, male Beagle dog, pretreated with
pentagastrin. 2 mg/kg, 5 min iv infusion, 9:1 PEG:EtOH, n = 5. 1
d
e
f
mg/kg, 5 min iv infusion, 9:1 PEG:EtOH, n = 3. Dosed as a
g
nanosuspension. At steady state.
Compound 4 inhibited recombinant CYP3A4 with an IC50
of 0.51 μM after a 30 min incubation. A more comprehensive
assay22 was performed to assess the potential for time-
dependent inhibition of CYP3A4. The large KI of 82.5 μM
mitigated the impact of a robust Kinact of 0.47 min−1, with the
result indicating mild drug−drug interaction potential23 due to
CYP3A4 inhibition at the 110 mg (Cmax = 0.32 μM, 1000λ =
1.8 min−1) and the 446 mg (Cmax = 1.3 μM, 1000λ = 7.5
min−1) doses. In human liver microsomes, the compound
inhibited the activity of the CYP2C subfamily with single digit
micromolar IC50s, and IC50s against the rest of the CYP
isoforms tested were greater than 17 μM. PXR in vitro
transactivation by compound 4 was evaluated to assess the
potential for induction of CYP3A4-mediated metabolism, and
4 was found to have an EC50 of >2.7 μM, with an average Ymax
of 36% (10 μM rifampicin = 100%). Following up on this
Figure 2. Effect of 4 on Aβ species in cultured H4-APPsw cells. See
ref 8, Figure 3 for the general method, and ref 16, Figure 1 for
additional data.
result, CYP3A4 mRNA induction was assessed in cryopre-
served primary human hepatocytes. A low (16%) elevation of
CYP3A4 mRNA was observed at 1 μM, a concentration
approximating the projected Cmax of 4, whereas a moderate
(36−43%) elevation was observed at supra-physiological
concentrations (3.3−10 μM). Taken together, these results
supported further safety profiling.
C
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a
Cardiac safety was evaluated in multiple experiments.
Compound 4 was 6-fold less potent at hERG than compound
3, a result we interpret as a consequence of its reduced
lipophilicity.24 Telemetry data from unconscious rabbits
showed no change in QTcf and a 4 ms increase in QTcv
after a 3 mg/kg dose (16 μM exposure). Dosing at 10 mg/kg
(50 μM exposure) resulted in a 3 and 10 ms increase in QTcf
and QTcv, respectively. The exposure multiples over the
projected clinical Cmax were from 50- to 170-fold, consistent
with a minimal risk of hERG liability. During these
experiments, increased blood pressure and decreased heart
rate were observed at doses of 10 mg/kg and higher; however,
these effects were not seen in parallel experiments in conscious
rats at any dose studied. The hemodynamic effects were
attributed to the anesthesia used during the rabbit experiments.
Compound 4 was well tolerated in a 2-week oral repeat dose
toxicity study in rats at 10, 30, and 100 mg/kg. A minimal,
nontoxicologically significant bilirubin elevation was observed,
in-line with previous observations in mice and in contrast to
the results seen for 3. Subsequent in vitro profiling of bilirubin
transporter inhibition revealed, surprisingly, that compound 4
had an identical potency at UGT1A1 (1.4 μM) to compound
3. Additionally, compound 4 potently inhibited the organic
anion transporting polypeptide 1B1 (IC50 = 66 nM). The lack
of correlation between the potency at these transporters and
the differential in vivo bilirubin levels observed in 3 and 4 is
not currently understood; the hepatocellular necrosis uniquely
observed with compound 3 may confound a simple
interpretation. Findings from the two-week toxicity study
were limited to stress and reduced food consumption effects
for the high (100 mg/kg) oral dose group, with no Notch-
related goblet cell metaplasia in the duodenum, consistent with
the gamma-secretase modulator mechanism of action. Addi-
tionally, no hepatotoxicity or necrosis was observed.
Compound 4 showed a 48-fold margin over the projected
human efficacious exposure of 4 μM·h at the NOAEL of 30
mg/kg. Additionally, an acute oral dose of 300 mg/kg in dogs
was tolerated with no significant changes in bilirubin levels or
other clinical pathological assessments. The observed Cmax and
AUC in this experiment were 14 μM and 180 μM·h,
respectively, translating to a 43-fold margin in Cmax and 46-
fold in AUC to the projected efficacious clinical dose.
Furthermore, in a one-month toxicity study in dogs, the high
dose group showed a NOAEL to minimally significant
hyperbilirubinemia at 150 mg/kg (40 μM·h exposure). In
total, the toxicity profile supported the progression of
compound 4 in human clinical trials.
Scheme 1. Initial Synthesis of Compound 3
a
Reagents and conditions: (a) PhMgBr, THF, 0 °C to rt, 30 min, then
reflux, 2 h; (b) 6 N HCl, 100%; (c) 1:4 30% H2O2/HCO2H, 40 °C,
15 min, then add 1-phenylcyclopentene, rt, 4 h [Caution!: initial
exotherm], 84%; (d) N-(chlorocarbonyl)isocyanate, 58 °C, 1 h, then
130 °C, 45 min, 13%; (e) conc. NH3, 100 °C in sealed tube, 5 h,
100%; (f) POCl3, 110 °C, microwave, 1 h, 72%; (g) MeNH2, THF, rt,
69%; (h) 1:1 THF/HOAc, 75 °C, 47%, then separate enantiomers;
(i) 4-chloro-1H-imidazole, KOH, DMSO, 80 °C, 20 h, 42%; (j) Fe,
1:2 HOAc/EtOH, 100 °C, 30 min, 97%.
As the program progressed, a more concise synthesis of the
key pyrimidine dichloride was developed and used for the
preparation of compound 4, as outlined in Scheme 2.
Alkylation of ethyl p-fluorophenyl acetate 12 with ethyl-4-
bromobutanoate afforded diester 13, which then formed the
substituted cyclopentanone 14 via Dieckmann condensation.
Reaction with molten urea directly provided the pyrimidine
dione, which was taken forward in the previously described
a
Scheme 2. Medicinal Chemistry Synthesis of Compound 4
Compound 3 was synthesized as shown in Scheme 1,
starting with Grignard addition of phenylmagnesium bromide
to cyclopentanone, followed by dehydration and oxidation to
afford 2-phenyl cyclopentanone. Condensation with N-
(chlorocarbonyl) isocyanate (CCI)25 afforded compound 7
in low yield. Subsequent condensation with ammonia yielded
the pyrimidine dione, which was then reacted with phosphoryl
chloride to give dichloropyrimidine 8. Reaction with methyl-
amine in THF gave a ∼4:1 ratio of monoaddition products
favoring the desired 4-aminomethyl regioisomer 9. Aniline 11,
derived from the substituted chloro-nitrobenzene 10 by
nucleophilic aromatic substitution with chloroimidazole and
subsequent reduction of the nitro group, was combined with 9
under acidic conditions to yield compound 3 after resolution
by chiral HPLC.
a
Reagents and conditions: (a) ethyl-4-bromobutanoate, DMF,
Cs2CO3, 60 °C, 72 h, 37%; (b) NaHMDS, THF, 0 °C to rt, 2 h,
94%; (c) urea, 150 °C, then add ketoester, 16 h, 35%; (d) POCl3,
N,N-diethylaniline, 103 °C, 4 h, 77%; (e) MeNH2, THF, 2 h, 84%; (f)
H2SO4, NMP, 100 °C, 18 h, 66%, then separate enantiomers; (g) 3-
methyl-1H-1,2,4-triazole, KOH, DMSO, 80 °C, 6 h, 26%; (h) H2, Pd/
C, MeOH, 94%.
D
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ACS Medicinal Chemistry Letters
Letter
manner to penultimate 16. This route avoided the use of CCI,
which was both toxic and of limited commercial supply. The
yield of the final coupling with aniline 17 was improved by
using catalytic sulfuric acid in NMP, which afforded the desired
compound 4 after chiral chromatography. The absolute
configuration of 4, as its HCl salt, was proven by X-ray
diffraction.26
◊Ani Consulting, LLC, Madison, CT 06443.
□Fulcrum Therapeutics, Cambridge, MA 02139.
▼Sanofi, Waltham, MA 02451.
Author Contributions
All authors have given approval to the final version of the
manuscript.
Funding
The results from the phase 1 clinical trial of BMS-932481
have been reported.27 Analysis of both plasma and CSF
samples demonstrated a dose-dependent increase in Aβ1−37
and Aβ1−38, a decrease in Aβ1−42 and Aβ1−40, and no change in
total Aβ1−x after single oral doses of 10 to 1200 mg, and upon
multiweek daily dosing at 50 to 200 mg. BMS-932481 was well
tolerated when dosed acutely. ALT elevations were observed
after administration of 200 mg of BMT-932481 for 24 days,
which was hypothesized to be due to unexpected bioaccumu-
lation of the drug in the liver. Modeling the multiple ascending
dose data revealed that a ∼25% lowering of Aβ1−42 would be
achieved at an exposure deemed free of ALT elevation;
however, the decision was made to discontinue the develop-
ment of BMS-932481 due to the inability to safely escalate the
dose to achieve greater Aβ reduction.
To summarize, we have discovered a bicyclic pyrimidine
capable of modulating the activity of gamma-secretase to affect
reduction in Aβ1−42 and elevation of shorter Aβ peptides as a
potential treatment for Alzheimer’s disease. The acceptable
projected human dose and attractive preclinical safety profile
supported our decision to evaluate the clinical effect of a low
Aβ1−42/Aβ1−37/38 ratio in human subjects. A more detailed
accounting of the broader medicinal chemistry efforts leading
to the discovery of BMS-932481 will be reported in due
course.
Funding was provided by Bristol-Myers Squibb, who employed
all authors at the time this research was conducted.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the scientists at the Biocon Bristol-Myers
Squibb Research Center (BBRC) for the synthesis of key
chemical intermediates, Valerie Guss and Alan Lin for
conducting in vivo studies, and Edward Kozlowski for
performing chiral separations.
ABBREVIATIONS
■
GS, gamma-secretase;; BACE, beta-site APP-cleaving enzyme;
GSIs, gamma-secretase inhibitors; GSMs, gamma-secretase
modulators; hERG, human ether-a-go-go-related gene;
hUGT1A1, human uridine diphosphate glucuronosyltransfer-
ase 1A1; OATP1B1, organic ion transporting polypeptide;
APP, amyloid precursor protein; MAPT, microtubule-
associated protein tau; PSEN, presenilin; PXR, pregnane X
receptor; ALT, alanine transaminases
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■
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■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.8b00541.
Synthetic procedures and analytical data for 1−4, 6−9,
11, and 13−1728 (PDF)
AUTHOR INFORMATION
Corresponding Author
*Phone: 617-494-7270. E-mail: Kenneth.Boy@bms.com.
■
(6) Bulic, B.; Ness, J.; Hahn, S.; Rennhack, A.; Jumpertz, T.;
Weggen, S. Chemical biology, molecular mechanism and clinical
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ORCID
Kenneth M. Boy: 0000-0003-3188-8252
Lawrence R. Marcin: 0000-0003-0375-6252
Yong-Jin Wu: 0000-0002-3452-6292
Jianqing Li: 0000-0002-8445-9796
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Zhuo, X.; Snow, K.; Padmanabha, R.; Agler, M.; Esposito, K.; Harden,
D.; Prack, M.; Varma, S.; Wong, V.; Zhu, Y.; Zvyaga, T.; Gerritz, S.;
Marcin, L. R.; Higgins, M. A.; Shi, J.; Wei, C.; Cantone, J. L.; Drexler,
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Present Addresses
⧫Bristol-Myers Squibb, Cambridge, MA 02142.
∥Bristol-Myers Squibb, Princeton, NJ 08543.
§Bristol-Myers Squibb, Princeton, NJ 08540.
⊥Cantor Colburn, Hartford, CT 06103.
●Forma Therapeutics, Branford, CT 06405.
¶Yale University, New Haven, CT 06520.
○Amgen, Cambridge, MA 02142.
■Modulus Discovery, Inc., Tokyo, Japan.
△Bristol-Myers Squibb, Pennington, NJ 06534.
⬡Arvinas, New Haven, CT 06511.
⬢Editas Medicine, Cambridge, MA 02141.
E
DOI: 10.1021/acsmedchemlett.8b00541
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ACS Medicinal Chemistry Letters
Letter
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