Structure-based design, synthesis, and biological evaluation of dihydroquinazoline-derived potent β-secretase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.07.043

Structure-based design, synthesis, and biological evaluation of a series of dihydroquinazoline-derived β-secretase inhibitors incorporating thiazole and pyrazole-derived P2-ligands are described. We have identified inhibitor 4f which has shown potent enzyme inhibitory (K_i = 13 nM) and cellular (IC₅₀ = 21 nM in neuroblastoma cells) assays. A model of 4f was created based upon the X-ray structure of 3a-bound β-secretase. The model suggested possible interactions in the active site.

Full text of DOI:10.1016/j.bmcl.2012.07.043

Bioorganic & Medicinal Chemistry Letters 22 (2012) 5460–5465
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure-based design, synthesis, and biological evaluation
of dihydroquinazoline-derived potent b-secretase inhibitors
Arun K. Ghosh a,b, , Satyendra Pandey a,b, Sudhakar Gangarajula a,b, Sarang Kulkarni a,b, Xiaoming Xu a,b
,
⇑
Kalapala Venkateswara Rao a,b, Xiangping Huang c, Jordan Tang c
a Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States
b Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, United States
c Protein Studies Program, Oklahoma Medical Research Foundation, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Structure-based design, synthesis, and biological evaluation of a series of dihydroquinazoline-derived
b-secretase inhibitors incorporating thiazole and pyrazole-derived P2-ligands are described. We have
identified inhibitor 4f which has shown potent enzyme inhibitory (Ki = 13 nM) and cellular (IC50 = 21 nM
in neuroblastoma cells) assays. A model of 4f was created based upon the X-ray structure of 3a-bound
b-secretase. The model suggested possible interactions in the active site.
Received 8 May 2012
Revised 6 July 2012
Accepted 9 July 2012
Available online 20 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
b-Secretase
Alzheimer’s disease
Memapsin 2
Inhibitor
Design and synthesis
Dihydroquinazoline
b-Secretase (BACE1, memapsin 2) is an important molecular
target for the treatment of Alzheimer’s disease (AD).1 This mem-
brane-bound aspartic protease catalyzes the cleavage of b-amyloid
precursor protein (APP) leading to the formation of amyloid-b-pep-
tide (Ab) in the brain. The neurotoxicity of Ab leads to brain inflam-
mation, neuronal death, dementia, and AD.2,3 Early on, we designed
a potent substrate-based transition-state inhibitor 1.4 An X-ray
structure of 1-bound b-secretase led to the structure-based design
of a series of BACE1 inhibitors.5 Over the years, we and others have
designed a variety of BACE1 inhibitors incorporating novel pepti-
domimetic and nonpeptide scaffolds.6–8 A number of BACE1 inhib-
itors have been shown to reduce Ab-levels in transgenic AD mice.
Furthermore, we recently showed that administration of b-secre-
tase inhibitor GRL-8234 (2) rescued the decline of cognitive func-
important molecular interactions responsible for its high affinity.10
Based upon this reported X-ray structure, we have designed a
CO2H
O
H2N
O
OH Me
H
N
H
N
H
N
Me
O
H2N
N
H
O
O
O
HN
H
N
(Ki = 1.6 nM)4
1
Ph
CO2HO
CO2H
Me
SO2Me
N
OMe
OH
H
N
H
N
H
N
tion in transgenic AD mice.9 While the development of
a
clinically effective inhibitor has not yet emerged, important pro-
gress has been made with small-molecule inhibitors belonging to
different structural classes.1
In 2007, Baxter and co-workers reported an interesting class of
2-amino-dihydroquinazoline-derived BACE1 inhibitors.10 A repre-
sentative example is inhibitor 3a (Fig. 1) with a reported Ki of
11 nM. An X-ray structure of 3a-bound b-secretase provided the
Me
O
O
Ph
2 (GRL-8234,
Ki = 1.8 nM)9a
Me
N
O
N
O
N
(Ki = 11 nM)10
NH2
3a
⇑
Corresponding author. Tel.: +1 765 494 5323; fax: +1 765 496 1612.
E-mail address: akghosh@purdue.edu (A.K. Ghosh).
Figure 1. Structures of inhibitors 1–3.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.07.043

A. K. Ghosh et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5460–5465
5461
1. DiBAL-H
1. p-NO2-Ph-OCOCl
2. pyridine, THF,
Cy(Me)NH, Et3N
OMe
OH
O
N
N
H
Boc N
H
Boc N
H
Boc
2. Ph3P = CHCO2Et
3. H2, Pd-C
4. aq. LiOH, THF
Boc N
H
5
12
O
O
4
O
9
OH
90%
EDC, HOBt,
77%
1. TFA, CH2Cl2
2. Aldehyde 7,
NaBH(OAc)3
DIPEA, Cy(Me)NH
53% (2 steps)
70% (4 steps)
H
O
O
N
BocHN
O
O
N
NO2
N
H
NO2
7
6
O
O
62%
1.TFA, CH2Cl2
2. Aldehyde 7,
Na(OAc)3BH
13
(2 steps)
1. H2, Pd-C
2. BrCN, EtOH
75% (2 steps)
3c
O
N
1. H2, Pd-C
N
H
NO2
3a
2. BrCN, EtOH
84% (2 steps)
O
O
O
8
1. Boc2O, DMAP
2. Mg powder,
3f
MeOH, ultrasound
3. LAH, Et2O
Boc N
15
Ts N
CO2Et
H
H
1. Swern Ox.
14
OH
63% (3 steps)
OH 2. Ph3P=CHCO2Et
44% (2 steps)
OEt
Boc N
H
Boc
N
H
Scheme 2. Synthesis of urethane-derived inhibitors.
9
10
O
1. H2, Pd-C
53%
anol at reflux furnished dihydroquinazoline derivative 3a in 84%
yield. For the synthesis of inhibitor 3b, (R)-phenylglycinol derivative
9 was oxidized under Swern conditions and the resulting aldehyde
was reacted with (ethoxycarbonylmethylene)triphenylphospho-
2. aq.LiOH, THF
(3 steps)
3. EDC, HOBt,
DIPEA, Cy(Me)NH
rane in THF to provide a,b-unsaturated ester 10. Hydrogenation of
the ester over 10% Pd–C in ethyl acetate and saponification of the es-
ter provided the corresponding acid which was coupled with N-
cyclohexylmethyl amine to provide amide 11 in 53% overall yield.
Amide 11 was converted to dihydroquinazoline derivative 3b by fol-
lowing the same sequence of reactions as 3a.
N
Boc N
H
3b
O
11
Scheme 1. Synthesis of dihydroquinazoline-derived BACE1 inhibitors.
We have investigated the potential of various urethane deriva-
tives as BACE1 inhibitors. A representative synthesis of urethane
derivative 3c is shown in Scheme 2. Phenylglycinol derivative 9
was reacted with 4-nitrophenylchloroformate to provide the corre-
sponding mixed carbonate.12 Reaction of N-cyclohexylmethyl
amine with this mixed carbonate afforded urethane derivative 12
in 90% yield in two steps. Removal of the Boc-group with trifluoro-
acetic acid and reductive amination of the resulting amine with
aldehyde 7 furnished nitro derivative 13 in 53% yield, in two steps.
Hydrogenation of nitro compound 13 over 10% Pd–C in ethyl ace-
tate followed by exposure of the resulting amine to BrCN afforded
inhibitor 3c. Urethane derivatives 3d and 3e were prepared by an
analogous procedure using Boc-protected (R)-cyclohexyl glycinol
as the starting material. For synthesis of urethane 3f, racemic ami-
no ester 14 was prepared using a multicomponent reaction devel-
oped in our laboratory.13 Reaction of 14 with Boc2O in the presence
of DMAP in CH3CN at 23 °C afforded the corresponding Boc-deriv-
ative. Treatment of the resulting ester with magnesium powder in
methanol under sonication afforded the corresponding Boc-amino
ester.14 Reduction of the resulting ester with LAH afforded the
racemic alcohol 15 in 63% overall yield. This alcohol was converted
to urethane derivative 3f and amide derivative 3g as described
above.
number of functionalities and heterocyclic scaffolds, to make spe-
cific interactions in the b-secretase active site to improve enzyme
affinity and potency. Herein, we report the design, synthesis, and
evaluation of a series of potent 2-amino-dihydroquinazoline-
derived inhibitors incorporating urethanes and heterocycles such
as pyrazoles and thiazoles. A number of compounds exhibited po-
tent b-secretase inhibitory activity and displayed good potency in
cellular assays. To obtain molecular insight into the possible li-
gand-binding site of b-secretase, we have created an energy-mini-
mized model of 4f based upon the 3a-bound b-secretase X-ray
structure.
The synthesis of various dihydroquinazoline derivatives is
shown in Scheme 1. The Boc-protected (R)-cyclohexylglycine
methyl ester 4 was reduced by DIBAL-H at ꢀ78 °C and the resulting
aldehyde was reacted with (ethoxycarbonylmethylene)triphenyl-
phosphorane in a mixture of CH2Cl2 and methanol to provide the
corresponding
a,b-unsaturated ester. The ester was subjected to
hydrogenation over Pd–C for 12 h to provide the corresponding sat-
urated derivative. Saponification of the ester with aqueous LiOH
afforded the acid 5 in 70% overall yield. For the synthesis of quinaz-
oline derivative 3a, acid 5 was coupled with N-cyclohexylmethyl
amine to provide amide 6 in 77% yield. Removal of the Boc-group
was carried out by treatment with trifluoroacetic acid and the
resulting amine was subjected to reductive amination with alde-
hyde 710,11 to afford nitro compound 8 in 62% yield. Hydrogenation
of 8 over 10% Pd–C in ethyl acetate at 23 °C provided the corre-
sponding amine. Reaction of this resulting amine with BrCN in eth-
Based upon the X-ray structure of 3a-bound b-secretase, we
planned to incorporate various heterocyclic derivatives in place
of the methyl group in 3a to interact with the b-secretase active
site. We were particularly interested in designing inhibitors with
thiazole and pyrazole derivatives since these heterocycles contain

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A. K. Ghosh et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5460–5465
Table 1
Amines by reductive amination of Cy-NH2 and aldehydes
Enzyme inhibitory and cellular activity of inhibitors
a,b
S
N
S
N
Entry Inhibitor
Ki
IC50
(nM)
(nm)
R
Me
19
Me
16 R = Me
17
18
R = CHMe2
HN
HN
R = CH2OMe
Me
N
S
O
1.
2.
3.
4.
25
71
N
N
N
N
N
N
N
N
R
NH
Me
O
O
O
O
N
N
N
N
NH2
NH2
NH2
NH2
21
R = H
20
3a
3b
3c
HN
HN
22 R = Me
HN
23
Me
N
O
O
O
163.8
783
37.5
482
3400
ntc
S
N
Me
16, EDC,
HOBt, DIPEA
OH
N
Boc N
H
Boc N
H
Me
N
O
O
5
24
O
O
1. TFA, CH2Cl2
2. Aldehyde 7,
NaBH(OAc)3
65% (2 steps)
S
Me
N
Me
N
O
N
N
H
NO2
4b
O
25
3d
3e
Scheme 3. Synthesis of memapsin 2 inhibitors.
H
N
O
O
hydrogen bond donor and acceptor groups for interactions in the
enzyme active site. Also, these heterocycles are inherent to numer-
ous bioactive natural products and FDA approved therapeutic
agents.15,16 Accordingly we designed a number of inhibitors con-
taining thiazole and pyrazole derivatives. The synthesis of various
dihydroquinazoline derivatives are shown in Scheme 3. N-cyclo-
hexyl derivative 16 was prepared by reductive amination of the
corresponding 4-thiazolecarboxaldehyde17 and cyclohexyl amine.
Similarly, amines 17–20 were prepared from the corresponding
aldehydes.18–21 Various known pyrazole aldehydes22 were con-
verted to amines 21–23 by reductive amination with cyclohexyl-
5.
6.
7.
60
nt
N
O
N
NH2
O
Me
N
O
O
104
122
1100
N
O
N
NH2
3f
O
amine. For synthesis of dihydroquinazoline 4b, acid
5 was
Me
N
coupled with amine 16 in the presence of EDC, and HOBt to provide
amide 24. Removal of the Boc-group and subsequent reductive
amination with aldehyde 7 furnished nitro derivative 25 in 65%
overall yield. This was converted to quinazoline 4b as described
above. Other inhibitors 4c–4i were prepared following a similar
protocol as 4b.
O
nt
N
O
N
NH2
3g
a
b
c
IC50 was determined in neuroblastoma cells.
GRL-8234 exhibited Ki = 1.8 nM, IC50 = 2.5 nM in this assay.9a
Not tested.
The b-secretase inhibitory activity of various inhibitors was
determined against recombinant b-secretase using our previously
reported assay protocols.23 The results are shown in Table 1. As
can be seen, our synthetic dihydroquinazoline derivative 3a has
shown Ki value of 25 nM. The corresponding phenyl derivative
3b exhibited nearly a sixfold lower enzyme inhibitory potency.
We have then investigated the corresponding urethane derivative
3c. However, this inhibitor displayed nearly a fivefold loss of po-
tency compared to 3b. However, the corresponding cyclohexyl ure-
thane derivative 3d, improved potency by 20-fold over 3c (entry 4).
The presence of a methyl group is important as the cyclohexyl ure-
thane derivative 3e is less potent. We have also incorporated a tet-
rahydropyran ring in place of the cyclohexyl group in 3d. As
shown, racemic mixture (1:1) 3f has shown reduced potency over
cyclohexyl derivative 3d. We have also examined the effect of a
ring oxygen in carboxamide derivative 3g. This derivative too lost
nearly fivefold potency compared to cyclohexyl derivative 3a. We
have also evaluated the cellular inhibition of b-secretase in neuro-
blastoma cells.24 Inhibitor 3a has shown an average cellular IC50
value of 71 nM. The corresponding phenyl derivative displayed
an IC50 of 482 nM. The urethane derivative 3c was significantly less
potent compared to inhibitor 3b. Similarly, urethane derivative 3f
showed an IC50 value of 1.1 lM (entry 6).
Based upon the reported X-ray structure of 3a-bound b-secre-
tase, we have incorporated various thiazole and pyrazole-derived
ligands in an effort to interact with residues in the b-secretase ac-
tive site. As can be seen in Table 2, incorporation of a (2-methylthi-
azol-4-yl)methyl substituent in place of the methyl group in 3d,
resulted in nearly a 40-fold loss of enzyme inhibitory activity (entry
1). The corresponding amide derivative 4b also exhibited a loss of

A. K. Ghosh et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5460–5465
5463
Table 2
Enzyme inhibitory and cellular activity of inhibitors
a,
b
Entry
Inhibitor
Ki (nM)
1463
IC50
(nm)
S
Me
N
1.
ntc
O
O
N
N
N
N
O
O
N
N
N
NH2
NH2
NH2
4a
4b
4c
S
N
Me
Me
O
O
2.
3.
79
390
S
N
Me
O
N
104
nt
N
Me
S
N
4.
106
nt
O
O
N
N
N
N
O
O
N
N
NH2
4d
S
N
5.
144
nt
NH2
4e
S
N
OMe
O
O
O
N
N
N
6.
7.
8.
13
11
23
21
23
48
N
N
N
O
O
O
N
N
N
NH2
NH2
NH2
4f
N
N
N Me
4g
NH
4h
N
NH
Me
O
N
9.
39
51
N
O
N
NH2
4i
a
b
c
IC50 was determined in neuroblastoma cells.
GRL-8234 exhibited Ki = 1.8 nM, IC50 = 2.5 nM in this asay.9a
Not tested.

5464
A. K. Ghosh et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5460–5465
Figure 2. Stereoview of the model of inhibitor 4f (green carbon) with b-secretase. Possible hydrogen bonds between the inhibitor and b-secretase are shown in black dotted
lines.
potency over 3a (entry 2). Interestingly, this compound displayed
poor cellular b-secretase activity in neuroblastoma cells over 3a.
Introduction of a methyl group on the methylene side chain in 4b
resulted in 4c which showed a loss of potency (entry 3). Further-
more, chain elongation in 4d and incorporation of (2-isopro-
pylthiazol-4-yl)methyl substituent in 4e did not improve potency
(entries 4 and 5). Interestingly, incorporation of a methoxymethyl
substituent on the thiazole side chain in 4f resulted in nearly a six-
fold improvement of enzyme activity over 4b. Furthermore, inhib-
itor 4f has shown very potent cellular inhibitory properties in
neuroblastoma cells (entry 6). We have also investigated various
substituted pyrazolylmethyl groups (entries 7–9). Methyl substi-
tuted pyrazole derivative 4g is more potent than the unsubstituted
derivative 4h in both enzyme inhibitory and cellular assays.
Incorporation of methyl group on the pyrazole ring in 4i did not im-
prove potency over the N-alkylated or unalkylated derivatives.
To gain insight into specific ligand-binding site interactions, an
energy minimized model structure of 4f was created in the active
site of BACE1, based upon the crystal structure of 3a-bound b-secre-
tase.10 The conformation of 4f was optimized using the CHARMM
force field.25 As shown in Figure 2, 2-amino dihydroquinazoline
functionality forms a unique hydrogen bonding network with the
catalytic aspartic acids Asp32 and Asp228 and the (S)-cyclohexyl
group nicely filled in the S10-subsite as reported in the X-ray struc-
ture.10 The 2-methoxymethylthiazole moiety appears to fill in the
hydrophobic pocket in the S2-subsite. Furthermore, the methoxy
oxygen is within proximity to form a hydrogen bond with
Thr232. This may explain the sixfold enhancement of enzyme
inhibitory potency over the 2-methylthiazole derivative 4b. The
P1-cyclohexamide fits well into the S1-site of b-secretase.
Walters (Rosalind Franklin University of Medicine and Science) for
helpful discussions.
References and notes
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Acknowledgment
Financial support by the National Institutes of Health(AG 18933)
is gratefully acknowledged. We would like to thank Professor D. Eric

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