Discovery of oxadiazoyl tertiary carbinamine inhibitors of β-secretase (BACE-1)

Article abstract of DOI:10.1021/jm061046r

We describe the discovery and optimization of tertiary carbinamine derived inhibitors of the enzyme β-secretase (BACE-1). These novel non-transition-state-derived ligands incorporate a single primary amine to interact with the catalytic aspartates of the

Full text of DOI:10.1021/jm061046r

7270
J. Med. Chem. 2006, 49, 7270-7273
Letters
Discovery of Oxadiazoyl Tertiary Carbinamine
Inhibitors of â-Secretase (BACE-1)†
Hemaka A. Rajapakse,*,§ Philippe G. Nantermet,§
Harold G. Selnick,§ Sanjeev Munshi,|
Georgia B. McGaughey,# Stacey R. Lindsley,§
Mary Beth Young,§ Ming-Tain Lai,‡ Amy S. Espeseth,‡
Xiao-Ping Shi,‡ Dennis Colussi,‡ Beth Pietrak,‡
Ming-Chih Crouthamel,‡ Katherine Tugusheva,‡
Qian Huang,‡ Min Xu,‡ Adam J. Simon,‡ Lawrence Kuo,|
Daria J. Hazuda,‡ Samuel Graham,§ and Joseph P. Vacca§
Departments of Medicinal Chemistry, Structural Biology, Molecular
Systems, and Alzheimer’s Research, Merck Research Laboratories,
P.O. Box 4, West Point, PennsylVania 19486
ReceiVed September 1, 2006
Abstract: We describe the discovery and optimization of tertiary
carbinamine derived inhibitors of the enzyme â-secretase (BACE-1).
These novel non-transition-state-derived ligands incorporate a single
primary amine to interact with the catalytic aspartates of the target
enzyme. Optimization of this series provided inhibitors with intrinsic
and functional potency comparable to evolved transition state isostere
derived inhibitors of BACE-1.
Figure 1. Discovery of tertiary carbinamine derived inhibitors of
BACE-1.
requirement for CNS penetration, which effectively necessitates
the development of novel inhibitors because of the poor brain
penetration properties usually associated with transition state
isosteres.6 While potent inhibitors of renin and plasmepsin based
on piperidine templates have been reported, such non-transition-
state isostere derived inhibitors for BACE-1 inhibition remain
scarce.7
The discovery of intrinsically and functionally active hy-
droxyethylamine derived inhibitors of BACE-1, exemplified by
structure 1, has been reported in the literature (Figure 1).8,9
Because of the large number of hydrogen bond donors and
acceptors, 1 was susceptible to efflux by P-glycoprotein (P-
gp), and its passive permeability was not consistent with a brain
penetrant compound.10 As a result, we focused on systematically
replacing the amide and sulfonamide components with substit-
uents compatible with CNS penetration while maintaining
acceptable potency. Recently reported studies have shown that
the P3 amide could be replaced while maintaining high levels
of enzyme inhibition.11 The right-hand P1 amide was critical
for the observed BACE-1 activity and could not be deleted
without significant loss of potency because it formed two
important interactions with the enzyme: the amide carbonyl
with the Gln73 flap residue and the amide NH with the backbone
Gly230 carbonyl.
Models based on the X-ray cocrystal structure of 1 in the
BACE-1 active site indicated that replacement with an amide
mimic in the form of an oxazoline could maintain the flap
interaction.12 Accordingly, 2 was synthesized with a simplified
primary hydroxyl aspartate ligand and was shown to have weak
activity in the BACE-1 primary assay. Given the oxazoline’s
instability to mild aqueous acid, we hypothesized that an
impurity could be causing the observed â-secretase inhibition.
When 2 was subjected to catalytic aqueous TFA, clean conver-
sion to the tertiary carbinamine ester 3 occurred. Much to our
surprise, this unique aspartyl protease inhibitor motif displayed
significant enzyme inhibition.13 However, 3 proved to be stable
only at mildly acidic pH. Rearrangement to amide 4 occurred
Aging populations worldwide continue to increase the
prevalence and social burden of Alzheimer’s disease (AD).1
Currently marketed treatments have limited efficacy, leaving a
large unmet medical need in terms of true disease-modifying
therapies. The amyloid cascade has emerged as a widely
accepted hypothesis for the cause of AD. According to this
theory, processing of the amyloid precursor protein (APP) by
â-secretase (BACE-1) followed by γ-secretase releases the
peptide Aâ, which is thought to play a central role in the events
leading to the dementia and inevitable mortality associated with
AD.2 Given its upstream position in the amyloid cascade and
absence of known mechanism-based toxicity, BACE-1 appears
to be an attractive target for the treatment of AD.3
BACE-1 is a type I membrane associated aspartyl protease.
The inhibition of aspartyl proteases with druglike small mol-
ecules remains a formidable challenge.4 Transition state isosteres
such as hydroxyethylamines, reduced amides, statines, and
aminostatines are the most commonly utilized “warhead”
fragments that interact with the catalytic aspartates.5 The large
active sites of aspartyl proteases typically require high molecular
weight inhibitors to achieve acceptable levels of inhibition, and
pharmacokinetic optimization of such large structures often
proves challenging. While intense research efforts have focused
on aspartyl proteases as therapeutic targets, the only marketed
treatments are for the inhibition of HIV protease. Therapeutically
useful inhibition of BACE-1 is further complicated by the
† PDB files for the BACE-1/inhibitor 3 complex (PDB identifier 2lSO)
and the BACE-1/inhibitor 8 complex (PDB identifier 2lRZ) have been
deposited with the Protein Data Bank.
* To whom correspondence should be addressed. Phone: (215) 652-
5629. Fax: (215) 652-3971. E-mail: hemaka_rajapakse@merck.com.
§ Department of Medicinal Chemistry.
| Department of Structural Biology.
# Department of Molecular Systems.
‡ Department of Alzheimer’s Research.
10.1021/jm061046r CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/10/2006

Letters
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25 7271
Figure 2. BACE-1/inhibitor 3 complex with relevant enzyme amino
acid residue depicted in green.
Figure 3. Optimization of the tertiary carbinamines.
at physiological pH, and cleavage of the ester bond readily took
place at pH 1 and pH 10.
An X-ray crystal structure of 3 bound to the BACE-1 active
site was obtained via the soaking exchange of a weak ligand
(Figure 2).14 The central tertiary carbinamine formed interactions
with catalytic aspartates Asp32 and Asp228, as well as the
Gly230 residue of the BACE-1 enzyme (the heavy atom
distances are 2.7, 2.9, and 3.2 Å, respectively). The primary
hydroxyl group was within hydrogen-bonding distance of Asp32
(2.5 Å). The ester carbonyl was in proximity to the flap residue
Gln73 (3.2 Å). While simple amines have been reported as
BACE-1 inhibitors,5 the connectivity of the benzylic appendage
filling the S1 pocket is transposed by one atom for inhibitor 3,
which represents an unprecedented vector for filling this pocket
of BACE-1. Comparing the bioactive conformations of inhibitors
1 and 3 illustrated that the P1 phenyl rings were overlaid closely,
filling identical space in the enzyme active site despite the
differing trajectories.
Figure 4. Inhibitor 8 complexed with BACE-1, with relevant enzyme
Further inspection of the BACE-1 protein complexed with 1
and 3 revealed the gross enzyme structure to be highly conserved
except for one key difference: the catalytic aspartic acid residue
Asp32 was rotated out of the plane defined by the second
catalytic aspartate Asp228 in the tertiary carbinamine enzyme
complex. The angle defined by Asp32,OD1-Asp,32Cγ-Asp,-
228Cγ-Asp228,OD2 was 84°. To the best of our knowledge,
this is the only reported example of a BACE-1 enzyme inhibitor
complex involving noncoplanar aspartates. This phenomenon
is highly unusual in the apo or inhibitor bound structures of
aspartyl proteases, as the usual coplanar orientation of the
catalytic aspartates results in an intermolecular hydrogen bond.15
We sought to improve the stability and potency of this novel
class of inhibitors (Figure 3). Deletion of the ester carbonyl
provided the stable ether analogue 5. Predictably, the absence
of the ester carbonyl resulted in a potency loss. Surprisingly,
excision of the primary alcohol presumed to interact with Asp32
gave 6 with a 3-fold potency gain.16 Examination of the enzyme
inhibitor complex of 3 revealed that isomeric ester 7 could
access the flap residue. Ester 7 did recoup the potency, but the
R-amino ester motif proved to be unstable at physiological pH.
The superior potencies of 3 and 7 suggested that the optimal
avenue for improving potency without drastically increasing
molecular weight was to incorporate a flap interaction. In
addition, cocrystal structures of inhibitors 3, 5, 6, and 7 in the
BACE-1 active site consistently revealed that the C1-C4 region
of the linker was coplanar in the bioactive conformation.
Therefore, we hypothesized that a heterocyclic constraint of the
C1-C3 region could provide a more stable structure capable of
interacting with Thr72 and Gln73.
amino acid residue depicted in green.
We chose to incorporate a 1,3,4-oxadiazole, a well-known
ester mimic,17 into the linker of our inhibitors. The resulting
oxadiazole tertiary carbinamine inhibitor 8 displayed excellent
intrinsic and functional potency in our BACE-1 assays and
proved to be a stable entity. An X-ray crystal structure of 8
complexed with BACE-1 was obtained (Figure 4), and we
observed close homology between the tertiary carbinamine and
the P1, P2, and P3 substituents for inhibitors 3 and 5-8. The
incorporation of a five-membered heterocycle did result in minor
distortions of the linker region, but this was fortunately tolerated
from the potency perspective.
The closest distance from the oxadiazole nitrogen atoms to
flap residues Thr72 and Gln73 were observed to be 3.8 and 3.6
Å, respectively. While the distance and the geometry were not
optimal for a true hydrogen bond, we observed that the
oxadiazole ring was rotated out of the plane defined by the
central aryl scaffold with a dihedral angle of approximately 29°.
Calculations show that the lowest energy conformation places
the two aryl rings in the same plane.18 Hence, we hypothesize
that a weak interaction of the oxadiazole and the flap region
could be present. The observed potency enhancement could also
be attributed in part to rigidification of the linker.
In terms of inhibition of other aspartyl proteases by this novel
warhead, inhibitor 8 does show moderate selectivity versus
highly homologous enzyme BACE-2 (IC50 ) 620 nM) and
shows little inhibition of renin at 20 µM inhibitor concentration.
Related tertiary carbinamine analogues display no inhibition of

7272 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25
Scheme 1. Synthesis of Tertiary Carbinamine Inhibitorsa
Letters
implications of this observation are not fully understood in terms
of inhibitor design. Unfortunately, because of the presence of
the P2 sulfonamide and P3 amide, 8 was not predicted to be
brain penetrant based on our in vitro P-gp assay. The optimiza-
tion of the tertiary carbinamine derived BACE-1 inhibitors
toward achieving this goal is an ongoing effort.
Acknowledgment. The authors thank Joan Murphy for mass
spectral data, Steve Pitzenberger for assistance with the structural
assignment of 3, Carl Homnick for chiral separations, B. Wesley
Trotter and James C. Barrow for thoughtful proofreading of this
manuscript, and Bryan T. Mott for the described second-
generation synthesis of 8. PyMol, version 0.99, distributed by
DeLana Scientific LLC, was utilized to generate Figures 2 and
4.
a (a) Benzylserinediol, i-Pr2NEt, BOP reagent, CH2Cl2, 27%; (b) 5%
TFA, CH3CN/H2O, 80%; (c) Boc-NHNH2, EDC, HOAt, DMF, 95%; (d)
HCl, CH2Cl2, 100%; (e) N-Boc-R-Me-Phe-OH, CDI, then CBr4, Ph3P,
CH2Cl2, 75%; (f) HCl, CH2Cl2, 97%; (g) BH3, THF, 95%; (h) CBr4, Ph3P,
Im, CH3CN/CH2Cl2, 53%; (i) benzylserine diol, NaHMDS, DMF, 79%,
then ChiralPak AD separation; (j) (R)-R-Me-phenylalaninol, NaHMDS,
DMF, 74%; (k) (R)-N-Boc-R-Me-Phe-OH, Cs2CO3, DMF, 86%; (l) HCl,
CH2Cl2, 95%.
Supporting Information Available: Experimental procedures
for the synthesis of compounds 3-8. This material is available free
of charge via the Internet at http://pubs.acs.org.
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Synthesis of the inhibitors 3-8 began with the isophthalimide
derivative 9 (Scheme 1). Coupling with benzylserine diol gave
amide 4, which underwent acid-catalyzed N,O acyl migration,
providing an alternative route to inhibitor 3. Coupling of 9 with
Boc-hydrazine and acid mediated deprotection gave access to
the benzoyl hydrazide derivative of 9. Activation of (R)-N-Boc-
R-Me-Phe-OH with CDI, addition of the benzoyl hydrazide,
followed by dehydration with CBr4/Ph3P in the same pot
provided desired the oxadiazole.20 Deprotection of the Boc group
gave inhibitor 8. Acid 9 was transformed to the benzyl bromide
derivative 10 via borane reduction and treatment of the resulting
benzyl alcohol with CBr4/Ph3P. The ether bond of inhibitor 5
was constructed by the deprotonation of benzylserine diol with
base, followed by treatment with intermediate 10. Separation
of the resulting diastereomeric mixture on a chiral stationary
phase provided 5. Etherification with (R)-R-Me-phenylalaninol
under the same conditions provided 6. Esterification of (R)-N-
Boc-R-Me-Phe-OH with 10 utilizing Cs2CO3 as the base
followed by acid mediated Boc deprotection afforded 7 in high
yield.
In summary, we report the discovery of novel non-transition-
state isostere derived inhibitors of BACE-1. The central tertiary
carbinamine moiety interacts with three key residues of the target
enzyme: the catalytic aspartates Asp32 and Asp228 and the
carbonyl of Gly230. We also report a novel vector for accessing
the S1 pocket of BACE-1. Utilizing structure-based information,
this series was optimized to the stable tertiary carbinamine
oxadiazole 8, which has intrinsic and functional potency
comparable to evolved hydroxyethylamine inhibitors of BACE-1
exemplified by 1.
The “warhead” fragment represented by the tertiary carbi-
namine oxadiazoles has been significantly simplified in terms
of hydrogen bond donors and acceptors compared to transition
state isostere derived inhibitors. Additionally, the tertiary
carbinamine inhibitors cause a highly unusual “induced fit” of
the BACE-1 catalytic aspartates, twisting Asp32 such that this
residue is orthogonal to the plane defined by Asp228. The

Letters
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Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25 7273
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