Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2011.02.038

This Letter describes the de novo design of non-peptidic hydroxyethylamine (HEA) inhibitors of BACE-1 by elimination of P-gp contributing amide attachments. The predicted binding mode of the novel cyclic sulfone HEA core template was confirmed in a X-ray

Full text of DOI:10.1016/j.bmcl.2011.02.038

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1942–1947
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure based design, synthesis and SAR of cyclic hydroxyethylamine
(HEA) BACE-1 inhibitors
⇑
Heinrich Rueeger , Jean-Michel Rondeau, Clive McCarthy , Henrik Möbitz, Marina Tintelnot-Blomley,
Ulf Neumann, Sandrine Desrayaud
Novartis Institutes for BioMedical Research, Novartis Pharma AG, PO Box, CH-4002 Basel, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes the de novo design of non-peptidic hydroxyethylamine (HEA) inhibitors of BACE-1
by elimination of P-gp contributing amide attachments. The predicted binding mode of the novel cyclic
sulfone HEA core template was confirmed in a X-ray co-crystal structure. Inhibitors of sub-micromolar
potency with an improved property profile over historic HEA inhibitors resulting in improved brain pen-
etration are described.
Received 18 December 2010
Revised 9 February 2011
Accepted 10 February 2011
Available online 15 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Alzheimer’s disease
BACE-1
b-Secretase inhibitor
HEA
Hydroxyethylamine transition state
mimetic
Alzheimer’s disease (AD) is a devastating neurodegenerative
disorder characterized by a progressive decline in cognitive func-
tion. Amyloid-beta (Ab) peptide deposits and neurofibrillary tan-
gles are the two major pathologic hallmarks associated with AD.1
The perturbation in rate of formation and/or clearance of the Ab
peptide initiates a cascade of events leading to the formation of
neurotoxic oligomers, insoluble amyloid plaques that disrupt neu-
ronal function and lead to neuroinflammation, cell death and
memory loss.2 Ab is generated by the proteolytic processing of
the membrane bound amyloid precursor protein (APP) via two
consecutive cleavages, first by the b-site cleaving enzyme
The identification of small molecule inhibitors of aspartyl pro-
teases is challenging since the enzymes normally recognize 6–10
amino acids of their substrate for binding and selectivity. Inhib-
itors of most aspartyl proteases (renin, HIV) that have been
reported in the literature contain a central transition state (TS)
isostere as the key binding element flanked by N- and C-termi-
nal fragments resembling the corresponding peptide sequence.6
The highly peptide-like character of such inhibitors results in
borderline drug-like physicochemical properties (MW, log P,
polar surface area (PSA), Lipinski’s number of oxygen and nitro-
gen H-acceptors (NHA).7 This in turn translates into poor pharma-
cokinetic properties and low blood–brain distribution and
permeability glycoprotein (P-gp) mediated efflux.8 To mediate
brain Ab lowering by inhibition of BACE-1, the synthesis of tran-
sition state based inhibitors able to cross the blood–brain barrier
(BBB) presents a formidable challenge which requires the devel-
opment of highly permeable inhibitors with as few as possible
P-gp recognition sites.9
Recently, there have been reports surfacing in the literature
describing inhibitors with novel core templates to evade the poor
property space of traditional TS isostere based inhibitors.10,11
Noticeably, a strong influence of the basicity of the HEA TS mimet-
ics on P-gp mediated efflux and brain exposure has been demon-
strated by different investigators.12,13 The extent of the pKa
reduction however needs to be individually balanced against the
decline of cellular activity, since compounds with a pKa <6 do not
inhibit amyloid secretion in cell based assays.12
(BACE-1) followed by
form a b-secretase-derived C-terminal fragment of APP (bCTF),
which undergoes further cleavage by the -secretase to create Ab
c-secretase. APP is cleaved by BACE-1 to
c
isoforms ranging from 37 to 42 amino acid residues. Ab40 is the
most abundant isoform, while the plaques linked with ADpatho-
genesis consist primarily of aggregated Ab42. Inhibition of BACE-1
has emerged as an attractive therapeutic target for AD, since
BACE-1 knockout APP transgenic mice lacking Ab40/42, do not form
amyloid plaques and are viable and fertile.3,4 Recently, it has been
demonstrated that inhibition of BACE-1 in primates lowers the
production of Ab40 and Ab42 in cerebrospinal fluid.5
⇑
Corresponding author. Tel.: +41 61 6963255; fax: +41 61 6962455.
E-mail address: heinrich.rueeger@novartis.com (H. Rueeger).
Present address: Evotec UK Ltd, 114 Milton Park, Abingdon, Oxfordshire OX14
4SA, UK.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.02.038

H. Rueeger et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1942–1947
1943
We decided to generate compounds within a more restrained
HO
Br
O
chemical space (MW <450, C log P <4, PSA <90 Å2, NHA 65, pKa <7)
to allow the identification of compounds with CNS penetration.
With these constraints in mind, we initiated the structure based
design of cyclic HEA templates containing suitable attachment
points for direct extensions into the corresponding S20- and S1/S3
sub-sites to gain potency and selectivity (Fig. 1). A reduction in
conformational flexibility and number of sub-site interactions,
compared to current published hydroxethyl- (like OM99-2,
Fig. 2)14 and HEA dipeptide isostere inhibitors,10,11 will lead to an
improvement of the ligand efficiency.15 Comparison of X-ray crys-
tallographic data on different HEA inhibitors revealed that the
binding mode and cavity were highly conserved.16 In an iterative
process (Fig. 2) different 5–7 membered HEA ring templates teth-
ered with P1 and P20 substituent’s were docked using QXP with
the Flo modeling package17 and conformational energy and the
overall binding potential was assessed. The functional group (X)
was selected based on its capability to interact with the flap and
to lower the pKa.18 The modified templates were re-docked again
until inhibitors with the desired property profile were identified.
Candidate 1 and 2 from this design cycle (Fig. 3) were synthesized
N
H
OH
1
2
BACE1 IC50 55 µM
O
O
HO
Br
S
N
H
OH
BACE1 IC50 0.95 µM
Figure 3. Amino-pyranol 1 and amino-dioxo-hexahydro-thiopyranol derivative 2.
and the binding activity determined. Inhibitor
2 was co-
crystallized with BACE-1 (Fig. 5) to compare the binding mode with
the initial docking pose in Figure 4.
The co-crystal structure of BACE-1 in complex with 2 was deter-
mined at 2.4 Å resolution.19 The crystallographic data confirmed
that the designed binding interactions were fully formed, including
H-bonding with Asp32 and Asp228, as well as the phenolic-OH
with the backbone amide of Phe108. The embedded sulfone moiety
in the cyclic HEA template considerably lowered the basicity of the
amine (2, pKa 5.7 vs 1 pKa 7.1) and formed optimal H-bonds with
the flap residues Thr72 and Gln73. 2 binds to a closed conforma-
tion of the flap, similar to acyclic or macro-cyclic HEA inhibitors.20
Figure 4. Overlay of 2 (blue sticks) with hydroxyethyl dipeptide isostere inhibitor
OM99-2 (green sticks); the flap of BACE is omitted for clarity.
S1
S3
R3
O
H
N
N
H
N
H
O
O
H
R2
R2'
S2
S2'
O
O
O
O
Asp228
Asp32
Figure 1. Binding mode of HEA dipeptide isosteres.
O Flap
Thr72
N
Gln73
H
P1
X
P3
P2''
N
H
O
cyclic HEA
template
Figure 5. Co-crystal structure of 2 in complex with BACE-1.
H
O
O
O
O
Asp228
In addition, excellent hydrophobic contacts were observed in the
adjacent S1 and S20 pockets resulting in micro molar activity
Asp32
Figure 2. Design concept for sub-site linked cyclic HEA inhibitors.
(IC50 0.95 lM).

1944
H. Rueeger et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1942–1947
The pyran based inhibitor 1, not being able to form close inter-
deprotection in MeOH catalyzed by Cs2CO3 and Parikh–Doering
oxidation of the alcohol provided the protected amino-ketone 7
with the desired relative (3R,5S)-configuration. From this interme-
diate a stereoselective reduction of the ketone could be achieved
with LiAlH4 and N-deprotection provided the racemic core cyclic
sulfone HEA template 9. After attachment of the P0 side fragment
by reductive amination, the amino and hydroxyl group of 11
(Scheme 2) were transformed into the oxazolidinone 12a or 12b,
to permit the exploration of the P3 pocket with a wide range of
chemical transformations. The applied synthetic sequence to the
differently substituted P1 derivatives (Table 1, 14a–f) is illustrated
in Scheme 2.
The synthesis of enantiopure inhibitors was achieved by simu-
lated moving bed chromatography on ChiralPak-AD with the more
soluble N,O-acetal 17 (Scheme 3) prepared from racemic N-Boc
amino-alcohol 8. The aryl bromide 17 was then converted into
aldehyde 18 by a Suzuki cross-coupling with 2,4,6-trivinylcyclotri-
boroxane pyridine complex and subsequent ozonolysis of the sty-
rene derivative. The different P3 extensions (R2) were prepared
from the aldehyde 18 by Wittig olefination and subsequent cata-
lytic hydrogenation over Pd-C or by NaBH4 reduction. Removal of
the N-Boc protecting group with 4 N HCl in dioxane, hydrolysis
of the N,O-acetal and cleavage of the MeO-group with BBr3, gave
access to the amino-alcohol 19 and 21. After reductive amination
with the corresponding P20-aldehyde the final inhibitors 20a–f
(Table 1) and 22a–e (Table 2) were obtained.
actions with the flap, resulted in a 50-fold weaker activity. This
finding indicated that the optimal H-bonding interactions of the
sulfone with the Thr72 and Gln73 amides of the flap resulted in
a considerable binding contribution, whereas further docking
experiments did not predict such interactions in similarly substi-
tuted larger and smaller rings. Based on the results of these two
benchmark compounds, we selected the cyclic sulfone HEA as core
template and started to probe the S3 pocket by extensions from the
P1 phenyl ring (Table 1, 14–20) with minimal NHA and PSA contrib-
uting moieties to facilitate BBB penetration and minimize P-gp ef-
flux. The same principles were applied for the optimization of the
hydrophobic contacts in the S20 pocket (Table 2, 22a–e) to gain po-
tency and selectivity.
The stereoselective synthesis of this new class of cyclic sulfone
HEA inhibitors21 starting from dimethyl-3,30-thio-dipropionate 3 is
summarized in Scheme 1.
The methyl keto-ester formed by a Dieckmann condensation re-
sisted direct c-alkylation with benzyl halides. A Knoevenagel con-
densation, however limited to electron rich benzaldehyde
derivatives, gave access to the unsaturated keto-ester. Quantitative
oxidation of the thioether to the sulfone with mCPBA and subse-
quent hydrogenation over catalytic platinum provided the satu-
rated sulfone keto-ester 4 in 60% overall yield. A stereoselective
reduction of the keto-ester to the racemic hydroxyl-ester 5 with
the desired (3S,4S,5S)-configuration could not be achieved. An
alternative sequence via a stereoselective NaBH3CN reduction,
hydrolysis of the (4R)-hydroxy-methyl ester followed by a Curtius
rearrangement and N-Boc protection afforded crystalline 6, with-
out chromatographic purification at any intermediate step. O-
Our de novo design approach produced a moderately active lead
(2, IC50 = 0.95 lM) with a slightly improved ligand efficiency (0.31
vs 0.29) compared to HEA inhibitor 2422 occupying a similar chem-
ical space (PSA, NHA). A crystal structure of 2 with BACE-1 (Fig. 3)
Table 1
SAR of P3 modifications for racemic 14a–f and enantiopure compounds 20a–g and 23 compared against an acyclic HEA BACE-1 inhibitor 24
O
F
R2
O
O
N
O
R1
S
O
O
F
HO
S
N
H
O
OH
N
H
N
H
N
H
OH
14a-f racemic
OH
20a-g enantiopure
24 (Elan)
23
MDR1-MDCK Pb
MDR1-MDCK Pb
Efflux ratio PBL–AP/
PAP–BL
a
a
Compd R1
R2
C log P PSA
hBACE-1 IC50
hCath D IC50
M)
AP–BL
BL–AP
(Å2)
(lM)
(
l
(10ꢀ6 cm/s)
(10ꢀ6 cm/s)
14b
14c
14c
14d
11
H
H
H
H
OMe
OH
OH
OH
OH
OH
OH
OH
OH
H
Br
OnPr
CH2OnPr
Br
3.0
3.9
4.0
3.7
3.7
2.3
4.4
2.0
66
66
76
76
78
87
87
87
107
87
87
87
87
105
116
61
1.1
0.76
2.3
1.1
2.8
1.8
6.2
1.2
0.99
0.15
0.19
0.37
0.30
0.06
0.15
3.2
1.9
2.3
2.0
0.9
2.4
5.4
7.1
2.1
1.7
1.9
1.8
2.4
1.2
0.37
6.4
4.7
19
24
7.7
7.9
13
9.7
37
––
30
28
4.2
18
45
33
88
26
41
1.2
1.4
1.4
1.8
2.6
4.2
––
5.4
5.7
7.0
3.7
9.0
––
1.8
0.9
0.8
4.2
15
14e
14f
H
3-Me-Bn
CH2OH
(CH2)2OH 1.5
nBu
nPr
Et
20a
20b
20c
20d
20e
20f
20g
2319,21
2422
17
32
4.4
3.9
3.3
3.2
3.0
3.3
3.6
5.5
4.4
3.1
3.0
23
Br
11
OCONHMe Br
3.8
1.4
2.2
19
18
IC50 values for BACE-1 and cathepsin D inhibition, and inhibition of cellular release of Ab40 were determined as already described.20
a
Values are means of at least three experiments.
b
PAP–BL is the permeability across MDR1-MDCK cell monolayer in the apical-to-basolateral and PBL–AP in the basolateral to the apical direction.23

H. Rueeger et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1942–1947
1945
Table 2
SAR of P20 modifications
Br
O
O
Cl
N
HO
S
R
N
H
O
Cl
OH
20f
22a
22c
22d
22b
22e
21 R = H
b(10-
Efflux ratio PBL–AP/
PAP–BL
a
a
a
b
Compd C log P PSA
hBACE-1 IC50
hCath D IC50
Ab40 CHO IC50
MDR1-MDCK PAP–BL
MDR1-MDCK P
BL–AP
(Å)
(l
M)
(l
M)
(l
M)
(10ꢀ6 cm/s)
6 cm/s)
21
ꢀ0.4
1.8
3.2
1.7
3.6
2.6
3.2
101
87
87
100
87
96
>100
66
0.30
4.3
0.055
1.4
4.2
22a
20f
22b
22c
22d
22e
1.2
––
0.42
0.67
1.5
11
33
16
3.0
2.1
0.55
8.5
7.7
87
IC50 values for BACE-1 and cathepsin D inhibition, and inhibition of cellular release of Ab40 were determined as already described.20
a
Values are means of at least three experiments.
b
PAP–BL is the permeability across MDR1-MDCK cell monolayer in the apical-to-basolateral and PBL–AP in the basolateral to the apical direction.23
Br
O
O
Br
O
O
CO2Me
MeO
S
S
4
(S)
OH
S
MeO
a-d
3
5
CO2Me
CO2Me
CO2Me
O
4
3
5
e-h
f, g
O
O
Br
O
Br
O
O
Br
O
MeO
S
MeO
S
R1
S
j
i-
k
N-Boc
O
R2
NH
Boc
N
H
(R)
O
O
OH
(racemic)
7
8 (R1=OMe, R2=Boc)
9 (R1=OMe, R2=H)
10 (R1=OH, R2=H)
6
l
m
Scheme 1. Reagents and conditions: (a) NaOMe, Et2O, 25 °C; (b) 3-bromo-4-hydroxy-benzaldehyde, AcOH, pyrrolidine, EtOH-H2O 10:1, reflux; (c) mCPBA, CH2Cl2, 40 °C; (d)
H2, PtO2, THF, 25 °C; (e) NaBH3CN, iPrOH–AcOH 4:1, 40 °C; (f) 4 N NaOH–dioxane 1:1, 25 °C; (g) (i) DPPA, NEt3, dioxane, (ii) tBuOH, reflux; (h) (Boc)2O, NEt3, DMAP, 50 °C; (i)
Cs2CO3, MeOH, 25 °C; (j) Py-SO3, DMSO, NEt3, 25 °C; (k) LiAlH4, THF, ꢀ70 °C; (l) 4 N HCl in dioxane, 25 °C; (m) BBr3, CH2Cl2, 0 °C.
revealed an only partially occupied P3 pocket. We envisaged a sub-
stantial gain in activity with different P3 fragments through addi-
tional hydrophobic and H-bonding interactions. To our surprise
only a 10-fold increase in potency could be achieved with hydro-
phobic extensions (Table 1, 20c–d) compared to the P3 unsubsti-
2), a steep SAR was observed and only hydrophobic 3-aryl substi-
tuted P20 fragments demonstrated activity in the micro-molar
range. The most potency enhancing effect was observed with the
bulky 3-tert-butyl-benzyl P20 fragment, resulting in inhibitor 22c
with a five-fold increase in potency (IC50 = 0.055
l
M) over the 3-
tuted analog 14e, accompanied by
a
three-fold increase in
iso-propyl analog 20f (IC50 = 0.30 l
over cathepsin D.
M) and a ꢁ10-fold selectivity
selectivity. Insertion of P3 residues containing a strong hydrogen
bond donor (20a, 20b) or acceptor functionality (20g, 23) resulted
in equally to slightly more potent analogs, however at the expense
of a substantial increase in P-gp mediated efflux. The phenolic sub-
stituent on the P1 residue was originally selected to form an addi-
tional H-bond to Phe108 only possible in BACE-1 and not in
cathepsin D. However, the observed effect on potency and selectiv-
ity was minimal deduced by comparison of 14b and 20f. In
addition, the additional H-bond donor induced a three-fold in-
crease in efflux (14a vs 14e). The synthetic utility of the phenol
is further offset by the low metabolic stability in rat liver micro-
somes (Table 3), as well as its potential to undergo phase II
metabolism.
When administered in mice, no brain exposure was observed as
expected with the high efflux compound 23 (efflux ratio 19). Hav-
ing a C log P of 3.3, NHA of 8, and a PSA of 116 Å2, compound 23 did
not comply with Norinder’s rule of thumbs for good blood–brain
(BB) distribution (rule 1: PSA <75 Å2 and NHA 65 and rule 2: if
log PꢀNHA >0, then log BB is positive).8b On the other hand, sub-
stantial brain exposure was achieved with compound 20f (C log P
3.3) and 22c (C log P 3.6) having a 2- to 3-fold efflux ratio, a pKa
of 5.6, NHA of 5 and a borderline PSA of 87 Å2.
In summary, the de novo designed cyclic sulfone HEA inhibitors
residing close to the desired CNS descriptor space showed a
reduced P-gp liability compared to ‘historic’ HEA. Furthermore,
we could demonstrate that potent and selective BACE inhibitors
containing a low to medium P-gp efflux ratio could achieve
Of the extensive SAR work in P0 (>50 compds) of simple benzyl
substituent’s (a few representative examples are displayed in Table

1946
H. Rueeger et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1942–1947
HO
R2
nPrO
O
O
O
O
O
O
Br
O
O
S
S
S
S
f, g
or
i, j
k, g
g
N
N
N
N
H
H
OH
14a (R2 = H)
14b (R2 = Br)
O
O
OH
O
O
15
13
14d
h, g
d, e
O
Br
O
O
Br
O
O
Br
O
O
O
O
R1
S
MeO
S
S
MeO
S
a
b
N
H
N
NH2
N
H
OH
O
OH
OH
O
12a (R1 = OMe)
12b (R1 = OH)
14c
11
9
c
l, m
f, g
O
O
O
O
S
B(OH)2
O
O
S
HO
HO
S
MeO
n, c, g
N
N
H
N
H
OH
O
OH
O
16
14f
14e
Scheme 2. Reagents and conditions: (a) 3-isopropyl-benzaldehyde, NaOAc, NaBH3CN, CH2Cl2–MeOH 1:1, 25 °C; (b) CO(Im)2, DIPEA, DMAP, 1,2-dichlorethane, reflux; (c) BBr3,
CH2Cl2, 0 °C; (d) Tf2O, 2,6-lutidine, CH2Cl2, 0 °C; (e) HCOOH, nBu3N, (PPh3)2PdCl2, DPPP, DMF, 110 °C; (f) H2, 10% Pd–C, MeOH–THF, 25 °C; (g) KOSiMe3, THF, 50 °C; (h) n-PrOH,
Pd(OAc)2, 2-di-t-butylphosphino-1,10-binaphthyl, Cs2CO3, toluene, microwave 130 °C; (i) 2,4,6-trivinylcyclotriboroxane–pyridine complex, Pd2(dba)3, tBu3P, Cs2CO3, dioxane,
microwave 160 °C; (j) (i) O3, CH2Cl2–MeOH, ꢀ78 °C; (ii) NaBH4, MeOH, 25 °C; (k) NaH, 1-iodo-propane, DMF, 25 °C; (l) 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, PdCl2(dppf),
NEt3, dioxane, microwave 200 °C; (m) 2 N HCl, NaIO4, THF–H2O, 25 °C; (n) 1-bromomethyl-3-methyl-benzene, PdCl2(dppf), K2CO3, EtOH, microwave 120 °C.
Br
O
O
Br
O
O
Br
O
O
S
MeO
S
S
HO
MeO
a, b
g - h
R1
Boc
N
H
N
Boc
N
H
OH
O
OH
8
17
21 (R1 = H)
22a-g (see Table 2)
i
c - d
O
H
R2
O
O
O
O
HO
S
S
MeO
e - h
N R1
H
N
Boc
OH
O
19 (R1 = H)
20a-f (see Table 1)
18
i
Scheme 3. Reagents and conditions: (a) 2,2-dimethoxy-propane, pTsOH, CH2Cl2, reflux; (b) enantiomer separation on ChiralPak-AD (hexane-tBuOMe–THF 5:4:1);
(c) 2,4,6-trivinylcyclotriboroxane–pyridine complex, Pd2(dba)3, tBu3P, Cs2CO3, dioxane, microwave 170 °C; (d) (i) O3, CH2Cl2–MeOH, ꢀ78 °C; (ii) PPh3, MeOH, 25 °C; (e) wittig
reagents, KHMDS, THF, 25 °C; (f) H2, 10% Pd–C, MeOH–THF, 25 °C or NaBH4, MeOH, 25 °C; (g) (i) 4 N HCl in dioxane, 25 °C; (ii) 2 N HCl–MeOH 1:4, 25 °C; (h) BBr3, CH2Cl2, 0 °C;
(i) aldehyde of the corresponding P20 fragment, NaOAc, NaBH3CN, CH2Cl2–MeOH 1:1, 25 °C.
Table 3
Acknowledgements
Plasma and brain concentration in mice (dose: 2
l
mol/kg, iv)
Microsomal stability rat
Compd Plasmaa Braina 0.25 h Efflux
X-ray data collection of the BACE-1 complex with compound 23
was performed at the Swiss Light Source, Paul Scherrer Institut, Vil-
ligen, Switzerland. We are grateful to the machine and beamline
groups whose outstanding efforts have made these experiments
possible.
0.25 h (
lM)
(
l
M)
ratio
(t1/2 (min))
23
20f
22c
0.67
1.03
0.32
<0.05
0.21
0.18
19
3.0
2.1
4
3
6
a
Values are means of four animals.
Supplementary data
moderate brain exposure. Subsequent efforts to address the
remaining issues such as inadequate potency, selectivity and
metabolic stability of these new cyclic HEA inhibitors will be
reported in due course.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.02.038.

H. Rueeger et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1942–1947
1947
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