Discovery of (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796): A γ-secretase inhibitor with Aβ lowering activity in a transgenic mouse model of Alzheimer's dis

Article abstract of DOI:10.1016/j.bmcl.2007.04.082

We report on the design of benzodiazepinones as peptidomimetics at the carboxy terminus of hydroxyamides. Structure-activity relationships of diazepinones were investigated and orally active γ-secretase inhibitors were synthesized. Active metabolites cont

Full text of DOI:10.1016/j.bmcl.2007.04.082

Bioorganic & Medicinal Chemistry Letters 17 (2007) 4006–4011
Discovery of (S)-2-((S)-2-(3,5-difluorophenyl)-2-
hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-
benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796):
A c-secretase inhibitor with Ab lowering activity in a transgenic
mouse model of Alzheimer’s disease
C. V. C. Prasad,a,* Ming Zheng,b Shikha Vig,a Carl Bergstrom,a David W. Smith,a
Qi Gao,c Suresh Yeola,b Craig T. Polson,d Jason A. Corsa,d Valerie L. Guss,d Alice Loo,d,
Jian Wang,e Bogdan G. Sleczka,e Charles Dangler,f,à Barbara J. Robertson,d
Joseph P. Hendrick,d,§ Susan B. Robertsd and Donna M. Bartend,*
aDepartment of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute,
5 Research Parkway, Wallingford, CT 06492, USA
bDepartment of Drug Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute,
5 Research Parkway, Wallingford, CT 06492, USA
cDepartment of Analytical R&D, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway,
Wallingford, CT 06492, USA
dDepartment of Neuroscience Biology, Bristol-Myers Squibb Pharmaceutical Research Institute,
5 Research Parkway, Wallingford, CT 06492, USA
eDepartment of Bioanalytical Research, Bristol-Myers Squibb Pharmaceutical Research Institute,
Route 206 & Provinceline Road, Princeton, NJ 08543, USA
fDepartment of Exploratory Toxicology, Bristol-Myers Squibb Pharmaceutical Research Institute,
5 Research Parkway, Wallingford, CT 06492, USA
Received 12 March 2007; revised 24 April 2007; accepted 25 April 2007
Available online 30 April 2007
Abstract—We report on the design of benzodiazepinones as peptidomimetics at the carboxy terminus of hydroxyamides. Structure–
activity relationships of diazepinones were investigated and orally active c-secretase inhibitors were synthesized. Active metabolites
contributing to Ab reduction were identified by analysis of plasma samples from Tg2576 mice. In particular, (S)-2-((S)-2-(3,5-diflu-
orophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796)
was identified with an acceptable pharmacodynamic and pharmacokinetic profile. Chronic dosing of BMS-433796 in Tg2576 mice
suggested a narrow therapeutic window and Notch-mediated toxicity at higher doses.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Alzheimer’s disease (AD) is the major cause of dementia
in the aging population. Autopsy of brains from AD pa-
tients reveals the presence of extracellular plaques and
intracellular tangles, pathological hallmarks which are
used to confirm diagnosis of the disease.1 Over 20 years
ago, it was discovered that plaques are largely composed
of beta amyloid peptides (Ab).2 Although it was origi-
nally suspected that plaques were themselves the pri-
mary neurotoxic agents in AD, the focus has now
shifted to soluble oligomeric forms of Ab.3 Although
Keyword: c-Sectretase inhibitors.
*
Corresponding authors. Tel.: +1 203 677 6699; fax: +1 203 677 7702
(C.V.C.P); e-mail: Prasad.Chaturvedula@bms.com
Present address: Novartis Institutes for Biomedical Research Inc.,
250 Massachusetts Ave., Cambridge, MA 02139, USA.
Present address: Sanofi-Aventis 25 Great Valley Parkway Malvern,
PA 19355, USA.
à
§
Present address: Intra-cellular Therapies, Inc., 3960 Broadway, New
York, NY 10032, USA.
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.04.082

C. V. C. Prasad et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4006–4011
4007
the majority of Ab is the 40 amino acid form (Ab40),
Ab42 is more prone to oligomerization and is associated
with AD through rare mutations that lead to increased
Ab42 production.3,4 Ab is generated from a precursor
protein through sequential cleavages by BACE and
c-secretase, both of which are being actively pursued
as targets for the treatment of AD.5,6 c-Secretase is a
complex of either presenilin-1 (PS-1) or PS-2 with nicas-
trin, Aph-1, and Pen-2, and is an unusual aspartyl pro-
tease requiring two Asp residues in PS.6,7
dro benzodiazepinone 4 or benzodiazepinone 5 which
still maintain all the suspected necessary hydrogen-bond
interactions with c-secretase. A convergent approach to
the synthesis of the dihydro benzodiazepinone ring sys-
tem in 4 is shown in Scheme 1. Our initial attempts to
prepare 4 from the diazepinedione of 3 failed as the aro-
matic carbonyl group could not be reduced selectively.
A successful approach to the synthesis of 4 was based
on an intramolecular Mitsunobu reaction shown in
Scheme 1.
Several structurally diverse small molecule inhibitors
of c-secretase have been reported in the literature
using whole-cell c-secretase inhibition assays. These
inhibitors include peptidic PS1 inhibitors,8,9 semi-pep-
tidic inhibitors from the Elan/Lilly group,10,11 diaryl
sulfonamides,12,13 succinoyl-caprolactam derivatives,14
substituted cyclohexyl sulfones,15–20 N-(oxoazepanyl)ben-
zenesulfonamides, aminothia-zoles21, and 1,4-benzoxaze-
pin-3-ones.22 Several compounds are entering clinical
trials.10,23
Thus, treatment of 6 (prepared from isochroman-3-one)
with triphenylphosphine and diisopropylazo-dicarboxy-
late furnished the desired compound 7 in 60% yield.
Introduction of azide functionality followed by its
reduction under controlled conditions proceeded in
excellent yield to give the amine 9. The amine was then
coupled to N-3,5-(difluorophenylacetyl)-alanine using
EDC to give 10 in 75% yield. Exposure of 10 to trifluo-
roacetic acid resulted in removal of the N-terminal tert-
butoxycarbonyl group to afford 11 as an amine salt in
almost quantitative yield. Inhibitors 10 (IC50 = 24 nM)
and 11 (IC50 = 9.0 nM) displayed excellent potencies
thereby confirming the hypothesis that the aromatic car-
bonyl group of diazepinediones plays a passive role in
the enzyme–inhibitor interaction. In further studies,
compound 11 was selected for oral administration to
Tg2576 mice (Table 1). The brain and plasma ED50 val-
ues for Ab reductions 3 h after dosing were 26 and
5 lmol/kg, respectively.
In two previous communications,24,25 we chronicled our
research efforts exploring potent c-secretase inhibitors
1–3 using a cell based assay that measures Ab40 levels.26
In an attempt to improve the exposure of 1 in Tg2576
mice, the carboxy terminus of 1 was constrained. This
effort led to the discovery of diazepinedione peptidomi-
metic 3. Diazepinedione based compounds exhibited im-
proved efficacy in Tg2576 transgenic mice over their
triamide congeners, but were still inadequate due to
poor pharmacokinetic profiles and/or brain penetra-
tion.24 The potencies of 1 and 3 (Fig. 1) suggest that
the newly introduced tertiary amide bond in 3 may not
be involved in a productive interaction with the c-secre-
tase complex. Since the extra amide bonds may be detri-
mental to brain penetration, our starting point for
peptidomimetic design began with the diazepinedione
moiety. Removal of the carbonyl of 3 would yield dihy-
Low compound levels of 11 were observed in the brain
relative to the in vitro IC50 value, which suggested that
there might be an active metabolite responsible for Ab
reduction. Mass spectral analysis of plasma and brain
samples from Tg2576 mice detected metabolite 15
(Table 2) which results from oxidation of the diazepi-
none ring in 11. Brain and plasma concentrations
of 15 were similar to the levels of 11 in these samples
OH
R
R
F
F
NHBoc
O
a
O
N
O
Me
O
H
N
N Me
H
O
O
6
H
N
N
N
N
X
N
H
Me
H
O
Me
O
Me
O
O
b
Me
1: X = OH; R = H; IC = 1 nM
F
F
50
Boc
3: IC = 2 nM
50
2: X = H; R = F; IC = 2 nM
50
N
R
N
F
F
F
F
O
N Me
O
e, f
H
N
N
N
Me
O
N R
H
O
H
H
R
N
N
R
O
O
N
N
N
H
7: R = H
8: R = N3
9: R = NH2
N
c
10: R = Boc
11: R = H
N
Me
H
d
O
O
O
O
4
5
Scheme 1. Reagents and conditions: (a) (Me)HNNHBoc, catalytic
HOAc, 100 ꢁC, 12 h, 54%; (b) diisopropyl azodicarboxylate, PPh3,
THF, rt, 12 h, 60%; (c) KN(SiMe3)2, À78 ꢁC, THF, trisyl azide, then
HOAc, 61%; (d) 10% Pd–C, EtOAc, H2 (1 atm), 40 min, 98%; (e) N-
(3,5-difluorophenylacetyl)-L-alanine, EDC, HOBt, Et3N, DMF, rt,
2 h, 75%; (f) CF3CO2H–CH2Cl2, rt, 2 h, 98%.
Potential for H-bond
interaction
Potential for H-bond
interaction
Figure 1. Design considerations of diazepinediones based on H-bond
motif recognition.

4008
C. V. C. Prasad et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4006–4011
Table 1. Ab and compound levels 3 h after a single oral dose of 30 lmol/kg to Tg2576 mice, n = 7–10
Compound
Cell IC50 (nM)
Brain Ab (% inhibition)
Brain conc (nM)
Plasma Ab (% inhibition)
Plasma conc (nM)
11
15
25
40
41
42
43
9
6
51
54
92
90
91
29
4
3
2
5
6
4
6
12
0.5
3
80
75
98
88
86
1
3
1
2
2
205 42
199 57
1
280 29
133 12
2091 162
1959 190
2750 322
546 49
0.3
10
30
750
202 8
72 10
Not determined
Not dosed
Means SEM.
Table 2. Ab lowering activity in H4 cells following modifications at the amino acid and at the carboxy terminus
R3
O
R
H
H
N
N
Y
X
N
N
R2
H
R1
O
O
R1
R2
R3
a
IC50 (nM)
Compound
X
Y
R
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
H
H
H
H
H
H
H
H
H
H
O
H
H
H
H
H
H
H
H
H
H
O
3, 5-Difluorophenyl
3-Fluorophenyl
4-Fluorophenyl
3-Chlorophenyl
3-Pyridyl
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH(CH3)2
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
6
8
H
H
59
10
162
43
269
3
H
H
Cyclohexyl
2-Naphthyl
H
H
2-Thienyl
3-Thienyl
2-Furyl
H
H
1
H
24
1
3,5-Difluorophenyl
3,5-Difluorophenyl
3,5-Difluorophenyl
3,5-Difluorophenyl
3-Furanyl
H
H
H
OH
H
H
H
H
H
H
H
H
H
OH
H
H
H
H
H
H
H
H
H
H
H
OH
H
H
4
CH3
CH3
CH3
H
1.3
0.2
2
3,5-Difluorophenyl
3-Fluorophenyl
4-Fluorophenyl
2-Fluorophenyl
3-Thienyl
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
0.5
2
H
H
14
22
0.7
1.9
14
56
0.4
H
H
2-Thienyl
Cyclohexyl
H
H
Phenyl
Phenyl
H
H
a Values are obtained for diastreomeric mixture. Values are means of two experiments, with 16 data points in each experiment; intra-assay variance
<10% (na = not applicable). IC50s were determined using a cell based assay.24
(data not shown). The efficacy observed after dosing 15
(Table 1) supports the conclusion that it contributes to
the efficacy observed upon administration of 11.
epinones were synthesized from isopropylhydrazine
and ethyl o-formylphenyl acetate in 65% yield. 1-Substi-
tuted diazepinones were synthesized from acetophenone
and methylhydrazine in 50% yield. The amine salt 14
was coupled to various acid chlorides or carboxylic acids
to furnish the desired products in 60–85% yield.
The synthesis of diazepine-based inhibitors is shown in
Scheme 2. The synthetic scheme involved coupling
aminodiazepine 14 with N-protected amino acid using
amide bond coupling reagents. Amine functionality
was introduced into the diazepinone moiety 12 using
Evans’ electrophilic azidation of enolates with 2,4,6-tri-
isopropylbenzenesulfonyl azide (trisyl azide).27 Reaction
of ortho-formylphenylacetic acid and methylhydrazine
in refluxing ethanol furnished the requisite diazepinone
12 in 50% yield (Scheme 2). Structural changes at posi-
tion 1 and 3 of the constrained ring were also considered
for structure–activity relationships. 3-Substituted diaz-
c-Secretase inhibition data obtained for the inhibitors
15–38 are shown in Table 2. Comparison of the potency
of peptidomimetic inhibitors to their triamide congeners
1–2 demonstrated that the diazepinone was an effective
mimetic at the carboxy terminus. Within the series of
diazepinone-based inhibitors carrying N-methyl substit-
uents, modification of the N-terminal phenylacetyl
group was performed. Introduction of halogens (e.g.,
3,5-difluorophenylacetyl) improved potency. As the data

C. V. C. Prasad et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4006–4011
4009
inhibitor potencies were similar to those observed in
triamide series. (15 vs 30, 38, and 39.) In addition, the
role of the diazepinone asymmetric carbon on potency
was investigated. Compound 15 was resolved into pure
diastereoisomers, 15a and 15b, using chiral HPLC
(absolute stereochemistry not determined). As expected,
the isomers differed substantially in potency (15a:
IC50 = 2 nM; 15b: IC50 = 150 nM).
N
N Me
a
CHO
OH
O
R
O
12: R = H
b
13a: R = N3
13b: R = NH2
c
d, e
R3
1
Both compound 11 and its metabolite 15 demonstrated
similar efficacy after oral dosing in Tg2576 mice
(Table 1). Again, low compound concentrations of 15
suggested that a metabolite(s) might be at least partly
responsible for efficacy. Mass spectral analysis of plasma
samples detected the formation of hydroxylated metab-
olites which can occur through oxidation at the benzylic
position of the phenylacetyl moiety. As the oxidation pro-
cess generates an additional chiral center, isolation of
pure diastereiomers was necessary to determine the iden-
tity of the active species. The synthesis of each hydroxyl-
ated metabolite is shown in Scheme 3. Diastereomeric
mixture 39 was easily separated using a chiral HPLC (Chi-
ralcel OD 50 · 500 mm column, 20 lm particle size as a
stationary phase and 5% EtOH in heptane as mobile
phase) into pure diastereomers 39a and 39b. Each isomer
was subjected to trifluoroacetic acid (TFA) mediated
deprotection, followed by coupling with either (R) or
(S) 3,5-difluoromandelic acid to furnish the desired
hydroxylated compounds 40 (BMS-433796), 41, 42, and
43 in good yield. The diastereoisomers differed markedly
in activity (Table 1). The stereochemistry of the most ac-
tive diastereoisomer 40 was confirmed by X-ray crystallo-
graphic analysis (Fig. 2). The dependence of potency on
stereochemistry of the hydroxyl functionality in 40–43 re-
flects a similar trend in the triamide series.25
2
O
N
O
R
H
f
H
N
N
N
3
H2N
Y
X
N
N
N
Me
R2
H
H
R1
O
R1
O
O
14
Scheme 2. Reagents and conditions: (a) (Me)HNNH2, EtOH, reflux,
1 h; (b) vacuum sublimation at 140 ꢁC, 1 h, 50% for two steps; (b)
KN(SiMe3)2, À78 ꢁC, THF, trisyl azide, then HOAc; (c) 10% Pd–C,
EtOAc, H2 (1 atm), 40 min; (d) Boc amino acid, EtOC(O)Cl, Et3N,
CH2Cl2, 0 ꢁC, 3 h; (e) CF3CO2H–CH2Cl2, rt, 2 h; (f) RCH2CO2H,
PyBop, EtN(i-Pr)2, CH2Cl2, 12 h, 60–85%.
suggest, introduction of water solubilizing group or
larger hydrophobic groups at the N-termini led to loss
of potency (21 vs 19 and 22). A similar trend was also
seen in the SAR of the hydroxytriamides. Inhibitors
22–24 were equipotent to 15, with a slight increase in po-
tency observed for the diazepinone with the 3-furanyl
and 3-thienyl N-capping groups. Thus, in addition to
halogenated aryl moieties, 3-furylacetyl functionality
was also desirable. Ketoamide 25 was found to have
comparable potency as the parent compound 15 against
c-secretase. Replacement of the N-methyl group with a
bulkier isopropyl group afforded an equipotent com-
pound (15 vs 26). Introduction of a methyl group at
the 1-position of the diazepine ring improved potency
(27 and 28). The role of a hydrophobic amino acid at
the central amide bond and introduction of an (S)-hy-
droxy group at the benzylic carbon were also investi-
gated. As expected, the trend and improvement in
Oral administration of 40 and 41 to Tg2576 mice
showed that they were significantly more effective at
lowering brain Ab than 11 and 15 (Table 1). The brain
Ab ED50 values were similar for 40 and 41 at 4 and
F
F
F
F
b, c
b, c
N
O
N
N
O
O
H
H
O
H
H
O
H
O
H
H
O
N
N
BocHN
N
N
N
N
N
H
Me
N
H
HO
Me
HO
Me
H
O
a
39b
42
43
N
O
N
BocHN
N
Me
H
O
39
a
F
F
F
F
b, c
b, c
HO
N
O
H
O
N
H
N
H
O
N
O
O
H
H
N
H
H
O
N
N
H
N
BocHN
Me
N
N
N
H
Me
HO
Me
H
O
O
39a
41
40
Scheme 3. Reagents and conditions: (a) separation on chiral HPLC; (b) CF3CO2H, CH2Cl2, rt, 3 h; (c) (R) or (S)-3,5-difluoromandelic acid, CH2Cl2,
PyBop, Et3N, 6 h, 65–82%.

4010
C. V. C. Prasad et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4006–4011
5 lmol/kg, respectively, compared with ED50 values for
11 and 15 of 26 and 48 lmol/kg, respectively. Com-
pound 40 reduced Ab in brain and plasma for 12 h after
a single dose, with recovery to near baseline in brain by
24 h and a 60% increase in plasma Ab at 24 h (Fig. 3).
This rise in plasma Ab occurred even at a time when
plasma levels of compound were below the level of
detection (<4 nM). Rises in plasma Ab have been re-
ported by others after administration of c-secretase
inhibitor in preclinical models and in humans.10,28
argy, weight loss, diarrhea, alopecia (loss of fur on the
back of the head), and mortality in a third of the ani-
mals. Histopathological analysis showed moderate to
marked hyperplasia of intestinal goblet cells in this
group. Although the 30 lmol/kg QD group did not
show any clinical signs, some animals had mild intestinal
hyperplasia. In addition to reducing Ab production,
c-secretase inhibitors are known to block the cleavage
of Notch, an important protein in development and
differentiation pathways.30 In vitro studies comparing
the activity of 40 in Notch and Ab assays26 show little
separation of activity with a Notch/APP(Ab) IC50 ratio
of 0.5. The clinical signs and histopathology are consis-
tent with a Notch mediated mechanism of toxicity.31
Tg2576 mice were also dosed with 40 for 14 days to
determine the effect of multi-day dosing on Ab lowering
and exposure. In one experiment, brain Ab was lowered
by 25% and 38% after 1 or 14 days of once daily (QD)
dosing at 4 lmol/kg. At a higher dose of 30 lmol/kg,
83%, 89%, and 98% inhibition was observed after a sin-
gle dose, 14 days of QD or twice daily (BID) dosing,
respectively. Along with no significant changes in activ-
ity, sub-chronic dosing did not lead to any accumulation
or reduction in drug levels through 14 days (data not
shown). In addition, when brain and plasma samples
were examined for possible metabolites, an active ketoa-
mide metabolite, 25 (Table 2), was detected at 20–40%
of parent levels in brain and plasma. Metabolite 25
was observed to be active when directly dosed in
Tg2576 mice as well (Table 1).
Compound 40 was also characterized in pharmacoki-
netic studies in male Sprague–Dawley rats. Following
a 10-min intravenous infusion at 2.3 lmol/kg in PEG-
400, the total body clearance of 40 was 5.2 0.82 mL/
min/kg (means SEM; n = 3), indicating low clearance.
The apparent terminal elimination half-life was
4.6 0.48 h. Oral administration of a PEG-400 suspen-
sion at 35 lmol/kg showed an oral bioavailability of
31% with prolonged absorption. The compound had
satisfactory metabolic stability in human liver micro-
somal preparations and was not an inhibitor of human
CYPs (IC50 > 100 lM).
The animals being dosed at 30 lmol/kg BID needed to
be terminated at 10 days due to toxicity, including: leth-
In summary, we have discovered a new constrained dia-
zepine ring system as a peptidomimetic at the carboxy
terminus of c-secretase inhibitors. The diazepine ring
system has fewer tertiary amide bonds over the previ-
ously disclosed 2,3-diazepin-1,4-dione ring system. Mass
spectral analysis of in vivo samples from Tg2576 mice
led to the identification of metabolites responsible for
inhibition of Ab production and to the design of a diaz-
epinone as a metabolically stable peptidomimetic at the
carboxy terminus. An inhibitor containing the new pep-
tidomimetic diazepine moiety coupled with (S)-3,5-diflu-
oromandelate at the amino terminus displayed
improved inhibition of Ab production in the brain over
its triamide congeners. Although compound 40 showed
excellent activity lowering brain Ab, frank toxicity was
observed with repeated dosing in mice. This toxicity,
likely due to a Notch mediated mechanism, limits the
usefulness of this compound as a therapeutic for the
treatment of AD.
Figure 2. ORTEP drawing of 40 with ellipsoids drawn at 35%
probability level and H atoms arbitrarily scaled. Carbon and hydrogen
atoms are not labeled.29
Brain
Plasma
180
**
Acknowledgments
160
140
120
100
80
We thank Charles Albright, Richard Olson, Jere Mere-
dith, Jr., and Todd Verdoorn for helpful comments.
60
40
**
References and notes
**
20
**
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0
**
0
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Time After Dose (hours)
Figure 3. Changes in Ab after a single oral dose of 40 at 30 lmol/kg in
Tg2576 mice. **p < 0.01.

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