Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind β-secretase in a N-terminal 10s-loop down conformation

Article abstract of DOI:10.1016/j.bmcl.2006.12.051

A series of low-molecular weight 2,6-diamino-isonicotinamide BACE-1 inhibitors containing an amine transition-state isostere were synthesized and shown to be highly potent in both enzymatic and cell-based assays. These inhibitors contain a trans-S,S-methyl cyclopropane P₃ which bind BACE-1 in a 10s-loop down conformation giving rise to highly potent compounds with favorable molecular weight and moderate to high susceptibility to P-glycoprotein (P-gp) efflux.

Full text of DOI:10.1016/j.bmcl.2006.12.051

Bioorganic & Medicinal Chemistry Letters 17 (2007) 1788–1792
Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind
b-secretase in a N-terminal 10s-loop down conformation
Shaun R. Stauffer,a,* Matthew G. Stanton,a Alison R. Gregro,a Melissa A. Steinbeiser,a
Jennifer R. Shaffer,a Philippe G. Nantermet,a James C. Barrow,a Kenneth E. Rittle,a
Dennis Collusi,b Amy S. Espeseth,b Ming-Tain Lai,b Beth L. Pietrak,b
M. Katharine Holloway,c Georgia B. McGaughey,c Sanjeev K. Munshi,d
Jerome H. Hochman,e Adam J. Simon,b Harold G. Selnick,a
Samuel L. Grahama and Joseph P. Vaccaa
aDepartment of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
bDepartment of Biological Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
cDepartment of Molecular Systems, Merck Research Laboratories, West Point, PA 19486, USA
dDepartment of Structural Biology, Merck Research Laboratories, West Point, PA 19486, USA
eDepartment of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA
Received 9 November 2006; revised 12 December 2006; accepted 13 December 2006
Available online 21 December 2006
Abstract—A series of low-molecular weight 2,6-diamino-isonicotinamide BACE-1 inhibitors containing an amine transition-state
isostere were synthesized and shown to be highly potent in both enzymatic and cell-based assays. These inhibitors contain a
trans-S,S-methyl cyclopropane P3 which bind BACE-1 in a 10s-loop down conformation giving rise to highly potent compounds
with favorable molecular weight and moderate to high susceptibility to P-glycoprotein (P-gp) efflux.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Beta-site amyloid precursor protein cleaving enzyme
(BACE-1) is a single-membrane associated aspartyl pro-
tease belonging to the pepsin family of proteolytic en-
zymes responsible for the processing of the amyloid
precursor protein (APP).1 Cleavage of APP by BACE-
1 is the rate-limiting step in the amyloid cascade leading
to the production of Ab40 and Ab42 peptide fragments.
In particular, Ab42 is the primary species that is thought
to be responsible for the neurotoxicity and amyloid pla-
que formation that lead to memory and cognitive defects
in Alzheimer’s disease (AD).2 Initial BACE-1 KO-mouse
studies,3a–c which showed no apparent adverse pheno-
type or detectable levels of Ab, continue to support the
rationale for the pursuit of BACE-1 inhibitors4a,b as a
potential means for therapeutic intervention for AD.
Previously, 1, which contains a reduced amide transi-
tion-state isostere as an aspartate interacting element,
in conjunction with a novel olefin P3-amide replacement,
was described as a potent BACE-1 inhibitor with good
cell permeability.5a,b However, despite the successful
substitution of the P3-amide within the isophthalate ser-
ies, inhibitors in this class remained susceptible to signif-
icant P-gp efflux, thereby limiting their ability to
penetrate the CNS. In an effort to develop BACE-1
P2
O
O
O
O
S
S
N
N
Remove P1' and P2' Amide
N
Alternate
P1'
constraints
O
O
HN
H
HN
N
HN
N
H
X
P2'
O
P3
IC50 = 20 nM
sAPPβ_NF = 23 nM
MW = 568
P1
Keywords: BACE-1 inhibitors; Alzheimer’s disease; 2,6-Diamino-
isonicotinamide.
X = OH, NH2
*
Corresponding author. Tel.: +1 215 652 3631; fax: +1 215 652
3971; e-mail: shaun_stauffer@merck.com
Figure 1. Reduced amide and isonicotinamide BACE-1 inhibitors.
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.12.051

S. R. Stauffer et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1788–1792
1789
inhibitors with improved CNS penetration and pharma-
cokinetic stability, we have investigated a series of trun-
cated amine and hydroxyl isosteres of type 2 (Fig. 1).
Our strategy was to remove prime-side elements from
amino-azides are described in Scheme 1. The requisite
trans-methyl cyclopropyl methyl amines, 5, were pre-
pared from all trans-crotonic acid 3 beginning with
EDC coupling using benzyl amine followed by cyclo-
propanation via Pd(OAc)2-catalyzed decomposition of
diazomethane. Subsequent chiral column chromatogra-
phy gave the preferred S,S-trans enantiomer,6 which
upon further functional group manipulation provided
the chiral amine 5. Amino alcohol and amino azide
intermediates (Scheme 1, 8a–c) were prepared in good
yield and selectivity (2S,3R configuration preferred)
using standard methods from either the appropriate
BOC-protected amino acid or amino epoxides.7 Inter-
mediate 7a (anti:syn >2:1), prepared in two steps via
Weinreb amide 6, was separated into its syn (1S,2S)
and anti (1S,2R) diastereomers and utilized to prepare
amino alcohols 8a (from anti isomer) or amino azides
8b where R3 = alkyl (from syn isomer). Epoxide 7b,
upon nucleophilic opening, was similarly utilized to pre-
pare intermediates where R3 = CH2OR.
0
0
inhibitors such as 1, in particular the P1 and P2 amide,
with the goal of further mitigating P-gp efflux and
improving CNS penetration. For this study, we chose
an N-terminal 2,6-diamino-isonicotinamide core with a
cyclopropylmethyl amine as an isosteric and non-olefin-
ic P3-amide replacement. Although a potency loss was
initially anticipated using a truncated prime-side desig-
n,5a the reduction in both the overall MW and the num-
ber of amide bonds was expected to favorably impact
P-gp efflux and pharmacokinetic stability.
Schemes 1 and 2 summarize the routes used to prepare
isonicotinamides 13–27. The intermediates required for
installation of the P3 cyclopropanes and right-hand P1
P3 Amines
O
1) EDC, BnNH2
Scheme 2 summarizes the convergent three-step cou-
pling and reduction sequence chosen to prepare target
compounds 13–27. Starting with methyl-2,6 dichloroiso-
nicotinate (9) and various alkyl sulfonamides, dilute Pd-
catalyzed N-arylation proceeded overnight to give the
monoarylated products of type 10. Saponification pro-
vided the key P2-containing isonicotinic acids 11. A
modified Pd-catalyzed amination reaction (4/5 + 11)
using DMA as solvent generated in 85–95% yield the
2-amino-6-sulfonamido isonicotinic acids 12.8 The ami-
nation products were subsequently coupled to amino
alcohol or amino azides 8a–c using EDC, which after
reduction and concomitant deprotection (R1 = Ph) pro-
vided the target isonicotinamides 13–27.
N
H
Ph
OH
2) CH2N2, Pd(OAc)2
3) Chiral column
4) BH3-THF
3
4
Opt. Capping
1) R1CHO, NaHB(OAc)3
2) H2, Pd(OH)2
1) BOP, R1CO2H
NH
2) BH3-THF
3) H2, Pd(OH)2
R1
5
P
1 Amino Azides/Alcohols
O
O
1) R3M
OCH3
EDC
BocHN
BocHN
7a
OH
N
2) NaBH4
MeOH
CH3
CH3NHOCH3
R2
R2
6
OH
R3
N3
OH
R3
1. HN3, PPh3, DEAD
2. HCl(g)
HCl
BocHN
H2N
H2N
8a
R3
R2
R2
R2
7a
anti:syn
8b
The inhibitory data of a select set of ‘non-capped’ iso-
nicotinamides (R1 = H) are shown in Table 1. Com-
pound 13, derived from 2S-3,5-difluorophenylalaninol,
represents the simplest transition-state analog wherein
X is a primary alcohol. This early example, with an
IC50 of 74 nM and MW of 482 amu, encouraged us to
evaluate additional prime-side analogs devoid of amide
functionality which would limit CNS penetration.
Extension of 13 with a simple butyl branch to give 14
resulted in a 5-fold improvement in potency for the dia-
stereomeric mixture.
>2:1(separate)
N3
O
1) NaOR
BocHN
7b
H2N
OR
2) Mitsunobu
3) HCl
R2
R2
8c
Scheme 1. Synthesis of P3 and P1 intermediates 5 and 8a–c.
O
O
R4
R5
N
S
Cl
R5NHSO2R4
Pd2(dba)3, Xantphos
N
N
K3PO4, dioxane, 100 o
C
O
O
Cl
Cl
(60-75%)
O
9
10
O
The 3S-OH stereochemistry shown for 14 was preferred
and is similar to that found in other known hydroxyeth-
ylene (HE) and aminoethylene (AE) transition-state
analogs for BACE-1;9a,b,c however, in contrast to these
transition-state isosteres there are no additional amides
present toward the prime-side. Unfortunately, despite
the good inhibitory activity in our enzymatic activity,
neither 13 nor 14 displayed significant functional activi-
ty in a sAPP_NF cellular assay.10 Replacing the hydrox-
yl group with an amine however, such as that found in
15, resulted in an inhibitor with good inhibitory potency
in the enzymatic assay and in the cellular assay. The
incorporation of a basic amine to engender cellular
activity against BACE-1 has been noted by others9c
and is thought to function by permitting the inhibitor
O
O
R5
N
S
N
R4
4/5, Pd[P(t-Bu)3]2
NaOH
K3PO4, DMA, 105 o
(85-95%)
C
MeOH/THF
(95%)
OH
Cl
11
O
O
O
O
O
R5
N
S
R5
N
S
N
R4
N
R4
1) EDC, 8a-c
OH
DIPEA, HOAt
2) R1 = Ph
O
N
N
NH2(OH)
R3
O
R1
HN
R1
H2, Pd(OH)2
12
13-27
EtOH, 60 o
C
R2
(50-75% two steps)
Scheme 2. Synthesis of trisubstituted isonicotinamides 13–27.

1790
S. R. Stauffer et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1788–1792
Table 1. SAR of P3 ‘non-capped’ inhibitors 13–20
S2
O
O
S
N
N
O
S3
X
N
S
R1
HN
R2
R3
S1' / S2'
(R1= H)
S1
Compound
X
R2
R3
H
BACE-1a (IC50 nM)
sAPP_NF (IC50 nM)
>20,000
F
13
OH
74
F
F
F
F
F
14b
15b
OH
n-Bu
n-Bu
13
9
>6700
110
NH2
16b
17b
18b
19b
20b
NH2
NH2
NH2
NH2
NH2
Ph
Ph
Ph
H
34
20
2
279
110
71
n-Bu
–CH2CH2CF3
n-Bu
11
32
38
S
CH3
54
S
a IC50 determinations were performed using an ECL-based assay10 and were run n > 2 with a CV < 0.3.
b Mixt. of trans methyl(cyclopropylmethyl)diastereomers.
to target acidic organelles wherein BACE-1 and sAPP
are co-localized. Truncation of the R3 group back to
hydrogen and substituting phenyl in P1 afforded 16,
resulting in a marginal loss in inhibition relative to 15
and 17. Alternatively, replacement of the R3 n-butyl
group with a trifluoropropyl chain (18) gave a ꢀ10-fold
improvement in inhibitory activity relative to 17; howev-
er, increased lipophilicity for this compound appears to
have limited its inhibitory impact in cells (measured
HPLC logPoctanol/water: logP > 3.5 for 18 vs measured
logP = 2.51 for 17).
Structure–activity relationships in P1 revealed a 4-fold
preference for a 2-thienyl substituent (19), thus permit-
ting truncation of the prime-side alkyl to 20, which in
cells proved to be nearly equipotent to 19. As a
BACE-1 inhibitor occupying the S1–S3 pockets (vide in-
fra) the potency of 20 is impressive considering its mod-
erate MW (465 amu).12 With respect to activity against
other aspartyl proteases, the series generally showed
moderate selectivity versus BACE-2 (>15-fold) and
excellent selectivity versus Cathepsin D (>5000-fold).
To gain an understanding of the binding mode for this
class of inhibitors, and in particular the interaction of
the R3 sidechain within the enzyme active-site, a co-crys-
tal structure of 19 with a human BACE-1 variant was
successfully obtained.13a,b The 19/BACE-1 complex
(Fig. 2) revealed the inhibitor occupied the S3–S1 sites
as predicted from modeling and previously obtained
structures containing similar hydrophilic P2 groups.13a
In addition, the primary amine was found to engage
both catalytic aspartates, Asp32 and Asp228, with hydro-
gen bonding contacts. With respect to S3, these inhibi-
Figure 2. BACE-1/19 view of S3/S1 (panel a) and view of prime-side
aspartic acid residue (32, 228) interactions (panel b).11

S. R. Stauffer et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1788–1792
1791
tors bind to and stabilize a 10s-loop down conformation
which is also found in the peptidic Val-P3 containing
OM99-2/BACE-1 crystal structure.14 The 10s loop,
which is known to be quite flexible, defines the size of
the S3 pocket and appears to vary depending on the P3
presentation.15 Relative to a similar 1,3,5-isophthalate
inhibitor5a bearing a (R)-a-methylbenzyl-carboxamide
With respect to P2 sidechain SAR, a propyl group at R5
(i.e., 22–23) resulted in a dramatic loss of inhibition in
whole cells, suggesting these compounds had exceeded
a lipophilic threshold disfavoring cell-penetration. How-
ever, in contrast to homologation at R5, increasing steric
bulk at R4 with an i-propyl group (i.e., 25) proved more
successful in retaining favorable cell permeability
properties.
sp
P3 residue in the S3 (sp = subpocket 10s-loop up), the
conformational change observed for this complex ener-
getically constitutes a >20-fold enhancement for the
inhibitor–enzyme complex, while fortuitously reducing
inhibitor MW by ꢀ80 amu and eliminating one amide
bond. Control inhibitors lacking the terminal trans-3S-
methyl group of the cyclopropane result in a potency
loss comparable in magnitude to the above comparison
and suggest that the presence of the terminal S3 methyl
group is responsible for most of the binding enhance-
ment. Relative to the OM99-2/BACE-114 crystal struc-
ture, the trans-methyl cyclopropane group occupies the
S3 pocket more deeply than the OM99-2 Val-P3 and ap-
pears to garner a number of additional key van der
Waals contacts in this region of the enzyme, including
the alpha carbons of Gly230, Thr231 and in particular
the methyl sidechain of Ala335. In addition, an alternate
rotamer for the sidechain of Leu30 is observed and ap-
pears to allow for optimal van der Waals contact with
the methylene portion of the cyclopropane ring.
The presence of a methyl capping group (R1 = CH3 vs
R1 = H, Tables 1 and 2) generally resulted in a reduction
in intrinsic and cellular inhibition (i.e., 5-fold 17 vs 21). In
contrast, capping R1 had a positive affect in reducing sus-
ceptibility to P-gp efflux. For example, in a cell-line
expressing human P-gp, 25 was a moderate substrate
for P-gp efflux (B/A–A/B: MDR1 = 13), while a closely
related non-capped analog, 17, exhibited significant efflux
(B/A–A/B: MDR1 > 50).18 An alternative capping group
that was highly beneficial for potency, although some-
what deleterious in terms of susceptibility to P-gp efflux
within the b-alkoxy series, was a methoxyethyl group as
illustrated by compound 27. In direct comparison with
compound 25, 27 was 4- and 12-fold more potent in terms
of enzymatic and cell-inhibition, respectively, and repre-
sents in the cell-based assay the only sub-100 nM
BACE-1 inhibitor within the ‘capped’ series.
In summary, we have shown that a series of isonicotina-
mides occupying the S1–S3 pockets in conjunction with
either a primary amine or alcohol are both highly potent
and selective against BACE-1. Although potency opti-
mization was readily achieved, susceptibility to in vitro
P-gp efflux remained a challenge when maintaining good
BACE-1 inhibition in whole cells. The incorporation of
a trans-methylcyclopropane P3 provides a significant
improvement in both potency and overall MW relative
to preceding isophthalate series investigated to date
and appears to originate from enhanced van der Waals
contacts within the context of a 10s-loop down BACE-
1 conformation. Further efforts incorporating and
retaining the favorable structural elements within the
isonicotinamide series into new inhibitor designs are
ongoing.17 These efforts and additional in vivo data
are forthcoming.
An additional somewhat unexpected feature for the
BACE-1/19 complex was that the R3 butyl sidechain
did not have a direct prime-side interaction in either
0
0
the S1 or S2 sites (Fig. 2, panel b). In an attempt to con-
formationally lock R3 into a favorable gauche confor-
mation which would poise the prime-side group
toward the more proximal S01 pocket, a b-alkoxyl substi-
tuent was incorporated.16 This modification is exempli-
fied within a series of ‘capped’ (R1 5 H) compounds
shown in Table 2 (21–27). Gratifyingly, introduction
of a methoxy methyl branch (24 vs 21) had a modest im-
pact on potency while reducing the overall MW. Exten-
0
sion of the hypothesized P1 group from methoxy (25) to
ethoxy (26) proved invariable in terms of BACE-1 inhi-
0
bition; an observation which was similarly noted in S1
by others utilizing HE isosteres.9b
Table 2. SAR of P3 capped inhibitors 21–27
O
R4
O
S
N
R5
N
O
NH2
R3
N
R1
HN
Compound
R1
R3
R4/R5
BACE-1a (IC50 nM)
sAPP-NF (IC50 nM)
21
22
23
24
25
26
27
CH3
CH3
CH3
CH3
CH3
CH3
MeO
n-Bu
n-Bu
CH3/CH3
CH3/n-Pr
CH3/n-Pr
CH3/CH3
i-Pr/CH3
i-Pr/CH3
i-Pr/CH3
31
39
67
12
24
24
6
589
>6700
>6700
173
CH3
CH2OMe
CH2OMe
CH2OEt
CH2OMe
845
402
66
a IC50 determinations were performed using an ECL-based assay (n > 2, CV < 0.3).9

1792
S. R. Stauffer et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1788–1792
9. (a) Ghosh, A. K.; Bilcer, G.; Harwood, C.; Kawahama,
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