Synthesis and structure-activity relationship studies of 1,3-disubstituted 2-propanols as BACE-1 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.05.072

A library of 1,3-disubstituted 2-propanols was synthesized and evaluated as low molecular weight probes for β-secretase inhibition. By screening a library of 121 1,3-disubstituted 2-propanol derivatives, we identified few compounds inhibiting the enzyme at low micromolar concentrations. The initial hits were optimized to yield a potent BACE-1 inhibitor exhibiting an IC ₅₀ constant in the nanomolar range. Exploration of the pharmacological properties revealed that these small molecular inhibitors possessed a high selectivity over cathepsin D and desirable physicochemical properties beneficial to cross the blood-brain barrier.

Full text of DOI:10.1016/j.bmcl.2012.05.072

Bioorganic & Medicinal Chemistry Letters 22 (2012) 4740–4744
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and structure–activity relationship studies of 1,3-disubstituted
2-propanols as BACE-1 inhibitors
⇑
Arun Babu Kumar, Jordan Micheal Anderson, Anthony Lester Melendez, Roman Manetsch
Department of Chemistry, University of South Florida, CHE 205, 4202 E. Fowler Ave, Tampa, FL 33620, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A library of 1,3-disubstituted 2-propanols was synthesized and evaluated as low molecular weight probes
for b-secretase inhibition. By screening a library of 121 1,3-disubstituted 2-propanol derivatives, we iden-
tified few compounds inhibiting the enzyme at low micromolar concentrations. The initial hits were opti-
mized to yield a potent BACE-1 inhibitor exhibiting an IC50 constant in the nanomolar range. Exploration
of the pharmacological properties revealed that these small molecular inhibitors possessed a high selec-
tivity over cathepsin D and desirable physicochemical properties beneficial to cross the blood–brain
barrier.
Received 11 March 2012
Revised 16 May 2012
Accepted 18 May 2012
Available online 6 June 2012
Keywords:
BACE-1
b-Secretase
Ó 2012 Elsevier Ltd. All rights reserved.
1,3-Disubstituted 2-propanol
Small molecule inhibitor
Blood–brain barrier
Cathepsin D
HEA
Hydroxyethylamines
The protease BACE-1 (also known as b-secretase) is a validated
target for the development of inhibitory compounds with potential
as a treatment for Alzheimer’s disease (AD).1–3 BACE-1 is an aspar-
tic protease which cleaves the amyloid precursor protein (APP), a
transmembrane protein, into a 42 amino acid peptide also known
as the amyloid b (Ab).4–6 Though, the exact mechanisms of events
leading to AD are still under scrutiny, recent reports suggest that
the insoluble Ab peptide is neurotoxic causing the neurodegenera-
tion typically observed in AD.6,7 Furthermore, it has been shown
that BACE-1 knockout mice not only produce Ab at significantly re-
duced amounts, but also do not develop the typical pathology of
AD.8–10 The inhibition of BACE-1, therefore, is considered to be
among the best strategies to reduce the undesired Ab production
and to treat AD.
In general, the development of efficacious BACE-1 inhibitors is
difficult due to the requirement that the inhibitory compounds
must not only be potent, but also display selectivity over other
aspartic proteases and have good physicochemical properties to
penetrate the blood–brain barrier.11 Furthermore, the elongated
BACE-1 active site dimensions challenge medicinal chemists to de-
sign a small molecule that efficiently occupies the active site.12,13
Peptidomimetics approach with transition state isosteres has been
one of the successful strategy for developing BACE-1 inhibitors.1–3
For example, hydroxyethylamines (HEAs) are known to broadly
mimic the transition state of aspartyl proteases’ substrates14–16
and they have been successfully incorporated in BACE-1 inhibitory
compounds.17–23 Macchia and co-workers previously reported the
study of a small library of eight hydroxyethylamine-containing
BACE-1 inhibitors exhibiting IC50 values in the low l
M range.19,20
Extensive docking studies with compound 1 suggests that the hy-
droxyl group tightly interacts with the aspartic acid residue Asp
228 positioning the carbazole moiety in the S1 and S2 subpockets,
while the 1-naphthylamine interacts in the S20 pocket via a
Tyr 198
O
H
S2
Cl
S2'
HN
N
O
H
Cl
S1
O
O
Abbreviations: AD, Alzheimer’s disease; Ab, amyloid b; APP, amyloid precursor
protein; HEA, hydroxyethylamines; BACE-1, b-secretase.
Asp 228
⇑
Corresponding author. Tel.: +1 813 974 7306.
E-mail address: manetsch@usf.edu (R. Manetsch).
Figure 1. Schematic representation of the main interactions between BACE-1
inhibitor 1 and the BACE-1 active site. Hydrogen bonds are shown as dotted lines.19
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.05.072

A. B. Kumar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4740–4744
4741
hydrogen bond between the nitrogen and tyrosine 198 and Van der
Waals interactions with tyrosine Tyr 198, valine Val 69, and
isoleucine Ile 126 (Fig. 1).19
and E13). Although, not all possible compound combinations were
prepared and tested, a selection of 121 1,3-disubstituted 2-propa-
nols was synthesized and tested to provide reliable information
about epoxide thiol combinations that yield promising BACE-1
inhibitors. The whole 1,3-disubstituted 2-propanol library of
As these 1,3-disubstituted 2-propanol derivatives possess low
lM potency, small molecule size and attractive synthetic tractabil-
ity we decided to conduct an extensive investigation on this molec-
ular scaffold for BACE-1 inhibition. A diverse set of indoles,
secondary amines and carbazoles derivatized with an epoxide
group was synthesized and further reacted with commercially
available thiols to yield a library of 1,3-disubstituted 2-propanols
(Fig. 2A). All reactions were performed at 50–100 mg scale and
the products were purified by column chromatography and subse-
quently characterized by 1H NMR, 13C NMR, and MS. Besides the
previously reported carbazole and indole containing scaffolds, the
library design was further expanded by a biphenyl (E9), a diph-
enylmethane (E10) and various secondary amines (E1, E11, E12
compounds was initially tested at 100 lM concentration using a
detergent-containing fluorescence resonance energy transfer
(FRET) based BACE-1 assay, which previously has been successfully
used in identifying BACE-1 inhibitors.24–26 Of these 121 com-
pounds, the compounds that showed activity at 100
lM were then
screened at both 50 and 25 M compound concentration. Although
l
this simple screening approach did not provide very precise inhibi-
tion data, it provided valuable structure–activity trends important
for hit optimization. The majority of the compounds that displayed
activity contain at least one extended ring system such as a carba-
zole,
a
tetrahydro-carbazole, or
a
2-phenyl-indole, while
A
F
Cl
F
Cl
N
N
N
N
N
N
N
SH
T3
SH
T5
SH
SH
T7
SH
SH
SH
O
O
O
O
O
O
O
T1
T2
T4
T6
E1
E2
E3
E4
E5
E6
E7
HO
NH2
O
O
OH
O
X
O
OH
O
SH
SH
SH
SH
SH
SH
T11
SH
T12
SH
T13
T8
T9
T10
N
O
O
N
N
N
N
N
N
SH
O
O
O
O
O
O
3
SH
T17
N
SH
E8
E9
E10
E11
E12
E13
T14
T15
T16
T18
ethanol/water (9:1),
reflux, 16h
OH
X
S
R
R'
X = N or O
121 combinations
B
Epoxides
E1
E2
E3
E4
E5
E6
E7
E8
E9
E10
E11
E12
E13
Compound
100 50 25 100 50 25 100 50 25 100 50 25 100 50 25 100 50 25 100 50 25 100 50 25 100 50 25 100 50 25 100 50 25 100 50 25 100 50 25
Concentration ( M)
T1
T2
T3
T4
T5
T6
T7
T8
2
69
56
85 64 35
86 85 79
0
2
2
10
54
86 41 48
87 92 56
62
64
63
15
23
3
94 82 51 95 86 68 89 84 67
1
8
10
5
0
82 69 56
24
99 87 65 100 93 68
92 99 68
91 81 55
81 73 62 45
7
76 65 45 27
11
24
15
1
92 89 73
67
74
5
15
90 71 40
75
71
38
2
0
T9
86 77 72 17
86 102 87 33
94 100 85
84 101 90
0
Thiol
T10
24
32
61
55
3
T11
T12
T13
T14
T15
T16
T17
T18
100 87 69 73
83 54 11 96 70 26 85 74 27 87 90 58 88 72 37 70
45
48
67
69
71
10
34
20
24
21
1
0
0
1
3
84 76 43 69
83 37
0
75
74
80 69 22 77 42 21 74
79 78 42
72
92 61 38
80 72 60
54
16
0
0
96 81 53
0
0
58
86 46
93 64 31 87 76 37
64
53
71
62
45
1
0
87
87 80 43
76 74 64
19
Legend: Percent inhibition is color coded
< 60 % 60% 70% 80% 90%
not tested
Figure 2. Synthesis and screening of a library of 1,3-disubstituted-2-propanols. (A) Preparation of the initial library starting from epoxides and commercially available thiols.
Of the 234 possible compounds, 121 analogues have been synthesized. (B) A set of 121 compounds have been tested initially at 100 M concentration. Compounds displaying
75% inhibition or greater have been further tested for BACE-1 inhibition at 50 and 25 M concentrations. The inhibition data for the screening at 100, 50, and 25
compound concentrations have been given as percent inhibition. Percent inhibition data is the average of two or more independent measurements.
l
l
lM

4742
A. B. Kumar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4740–4744
Table 1
Table 3
IC50 values of selected compounds identified in the screening
IC50 values of E7T18 analogues with various C4-linkers
Compound
BACE-1
IC50 M)
Cathepsin D
(
l
IC50
(lM)
R
E2T18
E3T5
E5T7
E6T3
E6T5
E6T12
E7T3
E7T11
E7T18
E8T9
E8T10
E8T15
E8T18
E10T5
E10T9
10.5 1.0
7.52 1.13
21.4 1.5
11.0 1.4
8.28 0.78
15.2 1.4
5.36 0.38
36.1 7.8
4.93 0.86
13.6 1.3
25.4 6.1
10.3 0.8
6.66 1.01
9.60 1.20
10.7 2.0
n.d.
>300
n.d.
n.d.
>300
n.d.
>300
n.d.
>300
n.d.
n.d.
n.d.
N
S
R'
Compound
R
R0
BACE-1 IC50
(lM)
Cathepsin D IC50 (lM)
9
10
11
H
OH
OH
OH
H
OH
4.31 0.66
6.74 0.50
10.1 1.0
>300
>300
n.d.
Next, studies have been undertaken to investigate the linker
connecting the carbazole or 2-phenyl-indole to the naphthyl ring.
This linker optimization focused on compound E7T18, since it is
the most potent compound. Initially, analogues have been synthe-
sized to evaluate whether the alcohol group is important for activ-
ity. Complete removal of the hydroxyl group in compound 2 is
combined with a decrease in activity (Table 2). Next, the enantio-
mers of E7T18 were synthesized independently and tested against
>300
>300
n.d.
compounds with an indole ring or small aromatic residues are less
potent. Furthermore, compounds containing basic amine were
completely inactive, though these comprise aromatic residues.
All compounds that showed an activity of 50% inhibition or
greater at 25 lM were then tested at multiple concentrations to
establish an inhibitory concentration IC50. The inhibitory concen-
BACE-1. The S enantiomer 3 with an IC50 of 5.39 lM seems to bind
to BACE-1 with an affinity similar to the racemic compound E7T18,
whereas the R enantiomer 4 was found to be slightly less active.
Importantly considering the standard deviations to be in the range
of 0.8–1.1 lM, the small differences between the IC50s of com-
trations were determined for 16 compounds resulting in a range
pounds E7T18, 3 and 4 support the previous docking studies by
Macchia and co-workers, in which the hydroxyl group of HEA
inhibitor interacts with Asp 238 independently of the alcohol’s ste-
reochemistry.19 With the idea to improve the interaction between
the compound’s linker and BACE-1, other groups were introduced
as replacements of the alcohol. The potency dramatically dropped
for ketone 5 possibly due to an unfavorable interaction between
the negatively charged Asp 238 and the ketone’s dipole moment.
Similarly, primary amines 6 and 7, as well as piperazine derivative
8 did not improve the activity against BACE-1.
Next, a small set of compounds was designed with the aim to
understand whether a compound with the linker length of 4 meth-
ylenes and an alcohol group would improve the potency in com-
parison to E7T18. Mono-alcohols 9 and 10, and diol 11 were
synthesized and tested for BACE-1 inhibition. Diol 11 showed de-
creased inhibition, while mono-alcohols 9 and 10 possessed single
of IC50 constants from 4.93 to 36.1
found to be E7T18 with an IC50 of 4.93
nyl-indole E8T18 was slightly less potent. One of the most promi-
nent bottlenecks in identifying lead molecules for BACE-1
inhibition is developing inhibitors with selectivity for BACE-1 over
other essential aspartyl proteases. Compounds displaying IC50s in
l
M. The best inhibitor was
lM (Table 1), while 2-phe-
the single digit lM range were further assessed for their selectivity
to inhibit BACE-1 over cathepsin D. Cathepsin D is an aspartyl pro-
tease with a catalytic domain similar to BACE-1 and is ubiquitously
present in almost all cells.12,27 Importantly, none of the tested com-
pounds showed any significant inhibition of cathepsin D up to
300 lM compound concentration rendering the best compounds,
E7T18 and E8T18, a selectivity of at least 50 fold. As reported by
Shoichet and co-workers, lead identification can be compromised
by promiscuous compounds that act as noncompetitive inhibitors
by aggregate formation leading to false positives.28,29 As put forth
by Seidler and co-workers, among the important criteria in assess-
ing aggregation-based promiscuity include non-specific activity
and high sensitivity to the presence of detergents.29 The fact that
the lead inhibitors show a good selectivity for BACE-1 over cathep-
sin D and the presence of 0.05% detergent in the assay buffer to dis-
rupt aggregates are good indicators that the lead inhibitors are
likely to be valid hits for BACE-1.
digit
positioned on the linker closer to the napthyl ring compared to
the carbazole moiety, demonstrated the IC50 value of 4.31
lM IC50 values. Compound 9, whose alcohol functionality is
l
M
and thus was slightly better than the initial hit E7T18. These stud-
ies on the linker (Tables 2 and 3) reveal that the linker has to be
sterically compact and can accommodate only one hydroxyl group.
Table 2
IC50 values of E7T18 analogues modified at the linker
R
N
R'
S
*
Compound
R and R0
BACE-1 IC50
(
lM)
Cathepsin D IC50 (lM)
2
3
4
5
6
7
8
R = R0 = H
7.52 1.13
5.39 0.81
7.98 1.02
>80.0
15.7 1.4
7.38 0.22
>50.0
>300
>300
>300
n.d.
n.d.
>300
n.d.
R = OH, R0 = H, S-configuration
R = H, R0 = OH, R-configuration
R = R0 = carbonyl
R = NH2, R0 = H, racemic
R = NHCH2CH2NH2, R0 = H, racemic
R = piperazine, R0 = H, racemic

A. B. Kumar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4740–4744
4743
M)
Table 4
IC50 values of bis-carbazole or bis-napthyl analogues with various linkers
Compound
Structure
BACE-1 IC50
0.71 0.10
(lM)
Cathepsin D IC50
>300
(l
OH
12
N
N
OH
S
S
13
14
>30
n.d.
n.d.
OH
N
N
>100
N
N
OH
15
8.82 0.50
>300
OH
Also it can be inferred that the linker chain length of four methy-
lene units is slightly better than three methylene units.
possess very poor blood–brain barrier permeability.32,33 Analysis
of the most potent compounds against BACE-1 revealed that all
analogues are in compliance with the rules dictated by Clark and
Lobell. Furthermore, logBB predictions clearly propose that the
blood–brain barrier permeability is in the acceptable range for
the most potent compounds such as E7T18, 9, and 12. Compound
E8T18, a close analogue of E7T18 in which the carbazole ring has
been replaced by the 2-phenyl-indole moiety, has excellent calcu-
lated blood–brain barrier permeability. Overall, these predictions
are encouraging and underline the potential of the herein
described compound series.
Finally, a set of compounds was prepared, in which the 2-propa-
nol linker was substituted in 1- and 3-positions with two carbazole
or two 1-napthylamine moieties. Surprisingly, the bis-carbazole 12
was very potent with an IC50 of 710 nM, while poor inhibition was
determined for bis-napthyl 13 (Table 4). Consequently, analogues
of 12 with 4 carbon linker, 14 and 15, were prepared to probe
the optimal linker length and the position of the alcohol group,
but they did not improve on the inhibition of BACE-1 over 12 with
3 carbon linker.
Besides potency against BACE-1 and selectivity over off-target
proteases such as cathepsin D, useful inhibitors must also have
acceptable physicochemical properties to penetrate the blood–
brain barrier. A selection of BACE-1 inhibitors has been evaluated
for blood–brain barrier permeability according to the rules pro-
posed by Clark and Lobell (Table 5).30,31 These rules predict that
a compound will possess acceptable blood–brain barrier perme-
ability if the compound’s molecular weight is less than 450 g/
mol, the polar surface area (PSA) <60–70 Å2, the number of nitro-
gens and oxygens (N + O) <6, and the parameter clogP-(N + O) >0.
Alternatively, using QikProp,32 the partition coefficient logBB,
which is defined as the ratio of the steady-state concentration of
the compound in the brain over the one in the blood (logBB =
log([compound]brain/[compound]blood)), has been computationally
calculated for the most promising compounds. Excellent blood–
In summary, we have conducted a study on a compound series
of 1,3-disubstituted 2-propanol for the inhibition of BACE-1. A se-
lected set of 121 compounds has been combinatorially prepared
and tested for inhibition of BACE-1 activity and hit compounds
such as E7T18, E7T3 and E8T18 have been identified to have
IC50s of 4.93, 5.36 and 6.66 lM, respectively. For the first time,
the selectivity of 1,3-disubstituted 2-propanols to inhibit BACE-1
over other essential aspartyl protease was tested. Promising hit
compounds have demonstrated to selectively inhibit BACE-1 over
cathepsin D with a selectivity factor of 50 or more. Subsequently,
structure–activity relationship studies focusing primarily on ana-
logues of hit compound E7T18 have been undertaken to further re-
fine the initial hit compounds. The screening results including the
detailed structure–activity relationship studies suggest that best
BACE-1 inhibition is observed if (a) a naphthyl or carbazole ring
in combination with an extended aromatic ring system such as a
carbazole or a 2-phenyl-indole is present to occupy the S1, S2,
S10, and S20 subpockets, (b) the linker has four methylene units,
which is marginally better than the linker with three units, (c)
the linker is sterically compact and it can accommodate only one
hydroxyl group. Further optimization efforts ultimately lead to
the most potent and selective compound, bis-carbazole 12, with
an IC50 of 710 nM against BACE-1 and a selectivity of >422 times
over cathepsin D.
The structure–activity relationship data with respect to the hy-
droxyl-containing linker supports the docking model proposed by
Macchia for HEA compound series.19 Additional studies are re-
quired, however, to fully understand the details of how compounds
such as hit E7T18 or bis-cabazole 12 interact with BACE-1 on an
atomic-level resolution. Nonetheless, the good potency in conjunc-
tion with high selectivity over cathepsin D and good blood–brain
barrier permeability predictions make the herein presented
brain permeabilities are predicted for compounds with
a
logBB >0.3, while compounds with a logBB <ꢀ1.0 are classified to
Table 5
Physicochemical parameters to predict the compound’s potential to penetrate the
blood–brain barrier
Compound
MW
N + O
PSA
clogP–(N + O)
logBB
E7T18
E8T18
E7T3
2
9
10
11
12
15
383.5
409.5
351.4
367.5
397.5
397.5
413.5
390.5
420.5
2
2
2
1
2
2
3
3
4
20.4
21.0
20.4
4.53
5.25
3.55
6.85
4.84
4.96
3.44
3.85
2.84
ꢀ0.013
0.374
0.091
0.287
ꢀ0.080
0.005
2.81
20.9
20.5
38.6
23.2
46.3
ꢀ0.285
0.009
0.091
All parameters have been calculated using the software QikProp (Schrödinger, LLC,
New York).32

4744
A. B. Kumar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4740–4744
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Compounds were prepared using synthetic procedures as re-
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tested for BACE-1was found to be P95% via HPLC analysis. Assay
for BACE-1 has been done using previously reported methodol-
ogy.24–26 Cathepsin D activity has been done using FRET-based as-
say kits from Anaspec (catalog no. 72170), which was validated by
testing with known inhibitor of Cathepsin D. For the testing of
compounds against BACE-1 and cathepsin D, measurements were
made in triplicates and inhibitory concentrations IC50s are reported
with the standard deviation.
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Funding
20. Bertini, S.; Asso, V.; Ghilardi, E.; Granchi, C.; Manera, C.; Minutolo, F.;
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Funding was provided by the University of South Florida.
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Supplementary data
Supplementary data (experimental details of the synthesis for
all compounds including 1H NMR, 13C NMR, and HR-MS for all
tested compounds) associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.05.
072.
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