2-Amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (β-site APP cleaving enzyme): Use of structure based design to convert a micromolar hit into a nanomolar lead

Article abstract of DOI:10.1021/jm0705408

A new aspartic protease inhibitory chemotype bearing a 2-amino-3,4- dihydroquinazoline ring was identified by high-throughput screening for the inhibition of BACE-1. X-ray crystallography revealed that the exocyclic amino group participated in a hydrogen

Full text of DOI:10.1021/jm0705408

© Copyright 2007 by the American Chemical Society
Volume 50, Number 18
September 6, 2007
Letters
Table 1. Inhibition of BACE by 1-3a
2-Amino-3,4-dihydroquinazolines as Inhibitors of
BACE-1 (â-Site APP Cleaving Enzyme): Use of
Structure Based Design to Convert a Micromolar
Hit into a Nanomolar Lead
cmpd
Ki (nM)
1
2
3
900
158
30
3a
11
Ellen W. Baxter,*,§ Kelly A. Conway,§ Ludo Kennis,†
Franc¸ois Bischoff,† Marc H. Mercken,† Hans L. De Winter,†
Charles H. Reynolds,§ Brett A. Tounge,§ Chi Luo,§
Malcolm K. Scott,§ Yifang Huang,§ Mirielle Braeken,†
Serge M. A. Pieters,† Didier J. C. Berthelot,†
Stefan Masure,† Wouter D. Bruinzeel,† Alfonzo D. Jordan,§
Michael H. Parker,§ Robert E. Boyd,§ Junya Qu,§
Richard S. Alexander,§ Douglas E. Brenneman,§ and
Allen B. Reitz*,§
Johnson & Johnson Pharmaceutical Research and DeVelopment,
LLC, Spring House, PennsylVania 19477, and Turnhoutseweg 30,
2340 Beerse, Belgium
Figure 1. Left: superposition of OM99-2 (peptidic inhibitor) and 1
in the active site of BACE-1. Right: ribbon diagram representation of
1 with the two catalytic aspartic acids highlighted bound into BACE-1
(maroon), showing the flap over the active site moved when compared
with BACE-1 when OM99-2 is bound in (turquoise).
ReceiVed May 8, 2007
Abstract: A new aspartic protease inhibitory chemotype bearing a
2-amino-3,4-dihydroquinazoline ring was identified by high-throughput
screening for the inhibition of BACE-1. X-ray crystallography revealed
that the exocyclic amino group participated in a hydrogen bonding array
with the two catalytic aspartic acids of BACE-1 (Asp32, Asp228).
BACE-1 inhibitory potency was increased (0.9 µM to 11 nM Ki) by
substitution into the unoccupied S1′ pocket.
protease BACE-1.3 This membrane bound type 1 protein
catalyzes the initial proteolytic cleavage of the amyloid precursor
protein (APPa) en route to the â-amyloid1-40(42) peptides. The
mouse homozygous knock-out shows significant reduction of
â-amyloid levels,4 and this gene deletion in the Tg2576 animal
model of â-amyloid overexpression results in the attenuation
of the cognitive deficit.5 BACE-1 has also recently been shown
to play a role in myelination in the peripheral and central nervous
system during development and may have cognitive and synaptic
functions independent of APP processing.6 Nevertheless, BACE-1
inhibitors have been shown to lower â-amyloid levels in the
brains of mice7 and thus may treat the etiology of the disease
and not just the symptoms.
Alzheimer’s disease (AD) is a chronic degenerative disorder
of the central nervous system, resulting in severe cognitive
deficits along with psychiatric complications.1 More than 20
million individuals suffer from this condition worldwide, and
this number is expected to grow dramatically. The current
standards of care are the cholinesterase inhibitors such as
galantamine, which are indicated for mild to moderate AD, and
the NMDA receptor antagonist memantine for the moderate to
severe form of the disease. A compelling molecular target
among the various strategies being pursued2 is the aspartic
* To whom correspondence should be addressed. Phone: 215-628-7119
(E.B); 215-628-5615 (A.R.). Fax: 215-628-4985 (E.B.); 215-540-4776
(A.R.). E-mail: ebaxter@prdus.jnj.com (E.B.); areitz@prdus.jnj.com (A.R.).
§ Johnson & Johnson Pharmaceutical Research and Development, Spring
House, PA.
A screen of our corporate compound collection resulted in
the identification of a variety of hits in the 1-10 µM range.
We focused SAR development on 2-aminoquinazoline 1, which
† Johnson & Johnson Pharmaceutical Research and Development, 2340
Beerse, Belgium.
10.1021/jm0705408 CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/08/2007

4262 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 18
Letters
Scheme 1a
Figure 2. Left: the 2-amino-3,4-dihydroquinazoline fragment of 1 and
the Asp32 and Asp228 sidechains of BACE-1, with H-bond distances in
Å between the Asp carboxylate oxygens and the hydrogens. Right: the
X-ray structure of 3a bound in to BACE-1, showing the R-cyclohexyl
substituent filling the S1′ pocket.
a Reagents and conditions: (a) MeNH-c-C6H11, EtOH, reflux; (b) H2,
Raney Ni, NH3/MeOH; (c) NaBH(OAc)3, CH2Cl2; (d) H2, Pd/C, thiophene,
MeOH; (e) BrCN, EtOH, reflux.
inhibited BACE-1 with a 0.9 µM Ki (Table 1). An X-ray
structure of 1 bound into the BACE-1 protein was obtained as
part of a collaboration with Astex Therapeutics. The BACE-1
protein used in the crystallography studies was prepared by
recombinant insect cell expression.8 The structure of 1 in the
active site of BACE-1 was compact, with the side chain bending
back onto itself in a hairpin turn orientation (Figure 1). This
allowed the N-cyclohexyl substituent to occupy the critical S1
binding pocket. In addition, the flap region of the protein
adopted an “open” structure in which the Tyr71CR carbon is
displaced by 4 Å relative to the peptidic OM99-29 bound into
BACE-1. Similar flexibility has been observed for the flap
region of other aspartyl proteases such as renin and HIV-1
protease.
Scheme 2a
An especially intriguing feature of this structure is the
exquisite hydrogen bonding array that 1 forms with the two
catalytic aspartates (Asp32, Asp228; Figure 2). Related 2-amino-
pyridines, 2,3-diaminopyridines, 1-aminoisoquinolines, and
2-aminoquinolines have been identified by the use of a fragment-
screening approach as BACE-1 inhibitors.10
To reinforce the hairpin conformation in the side chain, we
prepared 2, which bears a 1,3-disubstituted phenyl ring in the
side chain. This modification also incorporated 6-phenoxy
substitution instead of the 6-benzoyl group present in 1. A 6-fold
increase in potency for BACE-1 inhibition was observed for 2
(158 nM Ki) when compared with 1. Further examination of
a Reagents and conditions: (a) MeNH-c-C6H11, HBTU, NEM, DMF;
(b) TFA, CH2Cl2; (c) K2CO3, DMF, 120 °C, 1 h; (d) NaBH(OAc)3, CH2Cl2,
11; (e) SnCl2 2H2O, EtOH, reflux; (f) BrCN, EtOH.
Scheme 3a
a Reagents and conditions: (a) MeNH-c-C6H11, i-BuOCOCl, TEA,
CH2Cl2; (b) NH4OAc,NaBH3CN, MeOH; (c) NaBH3CN, HOAc, 13, MeOH;
(d) H2, 10% Pd/C, MeOH; (e) BrCN, EtOH, reflux.
the X-ray structure of 1 bound into BACE-1 revealed that the
vacant hydrophobic S1′ pocket could be filled by substitution
with S stereochemistry on the R-carbon of the side chain.
Compound 3 was prepared as a racemate initially and was found
to be a potent BACE-1 inhibitor (30 nM Ki). The enantiomers
of 3 were obtained independently, and the activity resided
predominantly in the S enantiomer as predicted (3a, 11 nM Ki,
Figure 2).
Chemistry. 2-Amino-3,4-dihydroquinazoline 1 was prepared
starting with the conversion of ethyl cyanoacetate 4 into amide
5, which afforded amine 6 after reduction (Scheme 1). Reductive
amination of 3-benzoyl-6-nitrobenzaldehyde 711 and 6 provided
benzyl amine 8. Reduction of the nitro group of 8 followed by
treatment with cyanogen bromide led to 2-amino-3,4-dihydro-
quinazoline 1.
The preparation of 2 was initiated by conversion of 9 to amide
10 and deprotection to provide 11 (Scheme 2). Nitrobenzalde-
hyde 12 was converted to phenoxy derivative 13.12 Reductive
amination of 13 and 11 afforded benzylamine 14, which was
converted to aminoquinazoline 2. The chemistry to prepare 3
(racemic) started with amidation of ketoacid 1513 to give 16,
followed by reductive amination to afford primary amine 17
(Scheme 3). Conversion to target 3 was conducted by the use
of the same sequence as for 1 and 2. The single enantiomers
of 3 were obtained via a synthetic strategy to prepare γ-sub-
stituted-γ-aminoacids devised by Smrcina and Majer,14 which
resulted in no detectable epimerization on a reaction scale of
up to 200 g.
a Abbreviations: APP, amyloid precursor protein; BACE-1, â-site APP
cleaving enzyme or Asp-2 or memapsin-2; NEM, N-ethylmorpholine.

Letters
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 18 4263
Scheme 4a
against BACE-1, which is an important target in the search for
new Alzheimer’s disease treatments. The exocyclic amino group
was shown to be involved in a hydrogen bonding array with
the two aspartic acids at the BACE-1 active site. X-ray
crystallography analysis of 1 (0.9 µM Ki) bound in to BACE-1
was critical in allowing us to design additional analogs with
improved potency. For example, because the side chain of 1
adopted an energetically unfavored hairpin conformation, 1,3-
phenyl disubstituted derivative 2 was prepared, which displayed
improved potency (158 nM Ki) relative to 1. Careful analysis
of the structure of 1 bound into BACE-1 revealed that the S1′
pocket could be accessed by (S)-R-substitution off of the side
chain, so we designed and prepared by (S)-R-(c-C6H11) deriva-
tive 3a, which had excellent potency for BACE-1 inhibition
(11 nM Ki). These structural modifications (2 and 3a) would
not have been given high priority for synthesis without the
insight provided by the crystal structure of 1 bound in to BACE-
1. We were able to transition from a micromolar hit to a
nanomolar lead suitable for extensive SAR development by the
use of ligand-BACE-1 crystallographic analysis.
a Reagents and conditions: (a) Meldrum’s acid, DMAP, EDCI, CH2Cl2;
(b) NaBH4, HOAc; (c) tol, reflux; (d) NaOH, acetone; (e) MeNH-c-C6H11,
HOBT, EDCI, TEA, DMF; (f) TFA, CH2Cl2; (g) 13, NaBH(OAc)3, CH2Cl2;
(h) H2, Pd/C; (i) BrCN, EtOH.
For the preparation of 3a, (R)-cyclohexylglycine 18 (>97%
e.e.) was treated with Meldrum’s acid under basic conditions
to afford 19, and the ketone functionality of 19 was subsequently
reduced with NaBH4 to provide 20. Thermolysis of 20 provided
lactam 21, which was saponified to 22, suitable for further
homologation to 3a (Scheme 4).
Pharmacology. Compound 3a was further examined in a
variety of assays to probe selectivity and suitability for further
consideration as a lead. It displayed modest selectivity for
BACE-1 over the aspartic proteases renin (2.7 µM IC50) and
cathepsin D (0.11 µM IC50) as well as the hERG channel (0.14
Acknowledgment. We thank Carlos Plata-Salaman, Kevin
Felsenstein, Chris Teleha, Bill Jones, Laura Reany, Scott
Ballentine, Sam Nortey, Jennifer Piesvaux, Tina Ross, Andrew
Darrow, Sergey Ilyin, Christopher Creighton, Umar Maharoof,
and Eric Strobel for helpful assistance and support. We also
acknowledge Astex Therapeutics for obtaining the X-ray crystal
structures.
Supporting Information Available: Chemistry experimentals
for the preparation of 1, 2, 3 and 3a. X-ray structure coordinates
for 1 and 3a bound in to BACE-1 have been deposited into the
Protein Databank (www.pdb.org, file codes 2Q15 and 2Q11,
respectively). This material is available free of charge via the
Internet at http://pubs.acs.org.
µM IC50). The Caco-2 apparent permeability coefficients Papp
A
to B and PappB to A values for compound 3a were determined
to be 0.28 × 10-6 cm/s and 3.38 × 10-6 cm/s, respectively.
The efflux ratio of 12.2 suggests that this compound is a PgP
substrate, although testing against PgP itself would need to be
done to confirm this hypothesis. Compound 3a exhibited
excellent potency in a cellular assay, which measures the
inhibition of Aâ1-40 secretion in CHO cells transfected with
the Swedish familial AD mutant APP (K670N/M671L). Ad-
ditionally, 3a lowered â-amyloid1-40 in plasma by 40-70% in
rats after p.o. administration (30 mg/kg), 3 h post-dosing.
Discussion. A variety of compounds have been reported that
inhibit BACE-1.3,15 Many of these are statine-like pseudo-
transition state inhibitors, and others have more dramatically
altered chemotypes such as the 2-aminoheterocycles recently
reported10 that are similar to the 2-amino-3,4-dihydroquinazo-
lines disclosed here. Considerable computational work has also
been conducted examining the BACE-1 active site in an effort
to design more potent inhibitors or add suitable substitution to
address ADME or other liabilities.16 There were several very
distinctive features of our 2-amino-3,4-dihydroquinazoline
chemotype. The 2-amino-3,4-dihydroquinazolines adopted a
compact structure bearing a hairpin turn of the side chain and
anchored at the active site by virtue of an extensive hydrogen
bonding array of the two catalytic aspartic acids with the
exocyclic amino group. As a consequence, the protein flap over
the active site was pushed away by a distance of about 4 Å
when compared to the structure of OM99-2 (peptidic inhibitor)
bound in to BACE-1. Because only the S1 pocket of the protein
was filled with initial 2-amino-3,4-dihydroquinazoline ligand
1 we were able to explicitly design several modifications that
served to improve potency. The hairpin turn was accommodated
by the incorporation of a structural constraint (e.g., 2), and the
S1′ pocket was filled by (S)-R-(c-C6H12) substitution.
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JM0705408