Discovery of ABT-957: 1-Benzyl-5-oxopyrrolidine-2-carboxamides as selective calpain inhibitors with enhanced metabolic stability

Article abstract of DOI:10.1016/j.bmcl.2019.05.034

Aberrant activation of calpain has been observed in various pathophysiological disorders including neurodegenerative diseases such as Alzheimer's Disease. Here we describe our efforts on ketoamide-based 1-benzyl-5-oxopyrrolidine-2-carboxamides as a novel series of highly selective calpain inhibitors mitigating the metabolic liability of carbonyl reduction. The most advanced compound from this new series, namely A-1212805 (ABT-957, Alicapistat) proceeded to clinical phase I studies.

Full text of DOI:10.1016/j.bmcl.2019.05.034

Accepted Manuscript
Discovery of ABT-957: 1-Benzyl-5-oxopyrrolidine-2-carboxamides as selec-
tive calpain inhibitors with enhanced metabolic stability
Katja Jantos, Andreas Kling, Helmut Mack, Wilfried Hornberger, Achim
Moeller, Volker Nimmrich, Yanbin Lao, Marjoleen Nijsen
PII:
S0960-894X(19)30331-2
https://doi.org/10.1016/j.bmcl.2019.05.034
BMCL 26454
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
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Revised Date:
Accepted Date:
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16 May 2019
17 May 2019
Please cite this article as: Jantos, K., Kling, A., Mack, H., Hornberger, W., Moeller, A., Nimmrich, V., Lao, Y.,
Nijsen, M., Discovery of ABT-957: 1-Benzyl-5-oxopyrrolidine-2-carboxamides as selective calpain inhibitors with
enhanced metabolic stability, Bioorganic & Medicinal Chemistry Letters(2019), doi:https://doi.org/10.1016/j.bmcl.
2019.05.034
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Discovery of ABT-957: 1-Benzyl-5-oxopyrrolidine-2-carboxamides as selective
calpain inhibitors with enhanced metabolic stability
Katja Jantos a,, Andreas Klinga,* Helmut Macka, Wilfried Hornbergera, Achim Moellera, Volker Nimmrichb,
Yanbin Laoc, Marjoleen Nijsenc
a AbbVie Deutschland GmbH & Co. KG, Neuroscience Research, Knollstrasse, 67061 Ludwigshafen, Germany
bAbbVie Deutschland GmbH & Co. KG, DMPK-BA, Knollstrasse, 67061 Ludwigshafen, Germany
cAbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064-6125, United States
———
ARTICLE INFO
ABSTRACT
 Corresponding authors. E-mail addresses: katja.jantos@abbvie.com (Katja Jantos), andreas.kling@abbvie.com (Andreas Kling).
Article history:
Received
Revised
Accepted
Available online
Aberrant activation of calpain has been observed in various pathophysiological disorders
including neurodegenerative diseases such as Alzheimer´s Disease. Here we describe our efforts
on ketoamide-based 1-benzyl-5-oxopyrrolidine-2-carboxamides as a novel series of highly
selective calpain inhibitors mitigating the metabolic liability of carbonyl reduction. The most
advanced compound from this new series, namely A-1212805 (ABT-957, Alicapistat) proceeded
to clinical phase I studies.
Keywords:
Calpain inhibiton
Cysteine protease inhibition
Ketoamide
2009 Elsevier Ltd. All rights reserved.
Alzheimer´s Disease
Calpains are intracellular, proteolytic enzymes from the
cysteine protease family constitutively expressed in the inactive
form. They are involved in several physiological processes like
cytoskeletal remodeling, modulation of signal transduction
pathways, platelet activation, cell differentiation and apoptotic
cell death. Calpain 1 (µ-calpain) and 2 (m-calpain) are
ubiquitously expressed and calcium-dependent with µ-molar or
m-molar calcium concentrations required for their respective
activation.1 Calpain activity is tightly controlled by the natural
protein inhibitor calpastatin, which only binds to activated
calpain. Overactivation of calpain has been observed in various
pathophysiological disorders, like ischemia of the heart, kidney,
lung, liver or the central nervous system (e.g. stroke),
inflammations, infectious diseases, muscular dystrophies,
cataracts of the eyes, diabetes, HIV disorders, injuries to the CNS
(e.g. brain trauma), Alzheimer's, Huntington's, Parkinson's
diseases and Multiple Sclerosis.2,3
neurodegeneration in different transgenic mouse models related
to AD.7-9 Therefore, inhibition of calpain represents an attractive
approach for the potential therapeutic treatment of Alzheimer´s
Disease.
Over the last two decades numerous calpain inhibitors have
been described,2,10-12 with the vast majority of these compounds
built in a modular concept containing a peptidic backbone and an
electrophilic warhead (Figure 1). This warhead, typically a
ketoamide or a (masked) aldehyde, covalently interacts with the
active site cysteine of calpain thus acting as covalent reversible
inhibitor. Major limitations of the calpain inhibitors described so
far were either their lack of selectivity versus other cysteine
proteases and poor drug like properties resulting in unfavorable
pharmacokinetics and no or insufficient bioavailability. Starting
from the prototypic calpain inhibitor A-705253 we identified
ketoamide-based 2-(3-phenyl-1H-pyrazol-1-yl)nicotinamides as
novel calpain inhibitors with improved profile.13
Activated calpain has been found in plaques and
neurofibrillary tangles of the Alzheimer´s Disease (AD) patients
brain, and has been shown to trigger multiple pathogenic
processes of AD such as synaptic dysfunction, β-amyloid
production, tau pathology and neurodegeneration.4-6
Overexpression of calpain has been shown to promote
amyloid plaque formation and neuronal degeneration, whereas
inhibition of calpain via overexpression of the natural inhibitor
calpastatin was shown to restore synaptic function and prevent

In particular A-953227 showed potent inhibition of calpain
combined with high selectivity versus related cysteine protease
cathepsins, other proteases and receptors. In addition, the
compound demonstrated broad efficacy in a set of preclinical
models relevant to AD. However, low stability against carbonyl
reductases led to significant formation of the inactive
hydroxamide metabolite in human, leading to low bioavailability
as well as short effective half-life in a Phase 1 study conducted.14
Table 1. Inhibition of calpain 1 and cathepsin selectivity for
compounds 3–11
Cal 1
Ki
--- selectivity ratios Cat/Cal ---
#
P2
[nM]
129
CatB
72
CatK
14
CatL
4
CatS
14
Fig. 1 General structure of ketoamide-based calpain inhibitors
showing the essential pharmacophores required for activity and
selectivity.
3
-
4
5
6
268
39
56
23
5
2
12
15
6
7
103
2
Here we describe our efforts on ketoamide-based 1-benzyl-5-
oxopyrrolidine-2-carboxamides as a novel series of calpain
inhibitors broadening structural diversity beyond the phenyl-1H-
pyrazol-1-yl)nicotinamide series as well as mitigating the
metabolic liability of carbonyl reduction.
22
17
528
In two papers Donkor et al. disclosed peptide-based aldehyde
inhibitors comprising proline mimetics in P2.15, 16 According to
the SAR reported there, cyclisation of the inhibitor backbone led
to significant enhancement of cathepsin B selectivity (compound
2, Figure 2), which raised our interest in these structures.
However, as an aldehyde warhead is not ideal from a drug-like
perspective, we prepared the corresponding ketoamide analogue
3 which showed slightly reduced calpain inhibition, but retained
high selectivity vs. cathepsin B. Based on this result we started to
further investigate this series with the objective to identify novel,
drug-like and selective calpain inhibitors structurally
differentiated from A-953227 and analogues described recently.
Our investigation started with modification of the central P2
part (Table 1). Shifting the sulfonamide group into the 5-
membered ring diminished calpain inhibition about twofold
(compound 4). Replacement of sulfonyl by carbonyl giving the
corresponding lactame led to about 6fold enhanced calpain
inhibition for the (R)-, but reduced activity for the (S)-epimer
(compounds 5 and 6; characterized as diasteromeric mixtures, see
experimental part).
7
8
9
50
101
64
23
72
14
1
4
4
13
3
3
2
21
56
10
11
82
46
15
4
2
6
4
13
41
-
21
Fig. 2 Structure and in vitro inhibition profile of 1 (A-953227) and compounds 2 and 3. Inhibition data for 2 were taken from reference
16. Selectivities (sel.) are reported as ratios cathepsin/calpain

2-OCH3,
6-CF3
Compound 5 also showed favorable selectivity versus the closely
related cathepsins B, K, L and S. Further P2 modification by
either incorporating 3-methylpyrrolidinone (7) or 1-methyl-
imidazolinone (8) as well as ring extension (piperidinone 9 and
pyridinone 10) showed an overall less favorable cathepsin
selectivity profile. At this stage we also cross-checked the impact
of P1 variation. Whereas additional phenyl substituents, e.g. 4-
methoxy or 4-trifluoromethyl, were well tolerated without
affecting overall selectivity (data not shown), the corresponding
P1 n-butyl analogue 11 showed retained calpain inhibition, but
reduced cathepsin selectivity, which was similar to the SAR
observed in the nicotinamide series.13 Based on these results we
36
51
120
387
395
20
shown, the SAR for calpain inhibition was quite flat and varied
for the different cathepsins of interest (16-20). Interestingly, 2,6-
di-substitution (20) resulted in the most potent and selective
analogue in this series.
Recently we reported on carbonyl reduction as a species-
specific metabolic liability of ketoamide-based calpain inhibitors,
resulting in low bioavailability in cynomolgus and human. This
pathway is reflected by low stability in liver cytosol (cytClint),
which can be used as an in vitro screening assay to select
analogues with enhanced stability versus carbonyl reduction.14
PK assessment of compound 5 displayed good oral availability in
rat (45%), but no bioavailability in cynomolgus monkey.
Cytosolic clearance was found to be highly unfavorable with
cytClint values of 185 and 270 µL/min/mg for cyno and human,
respectively, confirming again that low cytosolic stability reflects
low oral bioavailability in this species. To address this issue we
examined the possibility for P1´ extension in the oxopyrrolidine
series, since this concept had already been applied earlier by us to
mitigate carbonyl reduction as metabolic liability.
selected compound
5
containing the 5-substituted (R)-
oxopyrrolidine in P2 as lead for further optimization.
We then focused our efforts on variation of the P3 moiety and
systematically investigated SAR. A representative set of the
analogues prepared is shown in Table 2. Surprisingly, phenyl and
neopentyl analogue 12 and 13 displayed significantly diminished
calpain inhibition, whereas the corresponding 4-pyridyl and
cyclohexyl derivatives 14 and 15 showed only a 4-5fold reduced
calpain inhibition combined with less favorable cathepsin
selectivity. Phenyl substitution in 2- or 3-position was tolerated,
however, as illustrated by the set of selected examples
We prepared more than 50 substituted amides covering broad
chemical space and including various P1´ alkyl, o-alkyl, aryl and
hetaryl amides. Tertiary amides were not included since the NH
of the P1´ amide is essential for calpain inhibition. A selected set
of examples is shown in Table 3. In comparison to primary
amide 5 all analogues with P1´ extension showed significantly
enhanced cytosolic stability, but for most analogues calpain
inhibition was reduced in parallel. However, some P1´
modifications also had a positive impact on cathepsin selectivity,
an effect most pronounced for analogues 24 and 25 with aromatic
moieties in P1´. These analogues showed remarkable selectivity,
in particular for cathepsin B and S. However, due to the low
stability in liver microsomes further advancement was
discontinued.
Table 2. Inhibition of calpain 1 and cathepsin selectivity for
compounds 5 and 12 – 20
Overall, N-cyclopropylamide 22 displayed the best profile
balancing potency, selectivity and metabolic stability. To address
reduced calpain inhibition as a result of P1´ extension we re-
visited the P3 part of the structure and introduced various
substituted alkyl, aryl and hetaryl moieties. A set of selected
examples is shown in Table 4. Removal of P3 (27) led to
significantly reduced calpain inhibition. As observed previously,
benzyl in P3 was the most favorable moiety in this position, with
substituents in 2-position tolerated best. We therefore focused on
further investigating the SAR of different substituents and
substitution patterns. Most favorable results were achieved with
chloro, OCF3 and CF3 substituents in 2-position (28–30), leading
to enhanced calpain potency in a range of 1.5-2.5fold. However,
the most potent analogue in this set, compound 29, did not meet
our selectivity criteria for cathepsin L of >20fold selectivity.
Interestingly, the most potent and selective P3 moiety from the
P1´ unsubstituted amides (2-OCH3, 6-CF3–benzyl as found in
example 20, Table 2) in combination with P1´ cyclopropyl led to
a significant loss of potency (example 31). As the P3 benzylic
position was identified as metabolic hot spot in this series, we
tried to mitigate metabolism, either via additional substitution in
this position or introduction of heterocyclic residues with lower
lipophilicity. However, all analogues displayed reduced calpain
potency. Compounds 32 and 33 are shown as representative
examples with calpain Ki >500nM.
--- selectivity ratios ---
Cal 1
Ki
Cat/Cal
#
5
P3
R
[nM] CatB CatK CatL CatS
39
23
22
15
103
12
13
14
>1350
1350
180
28
23
16
6
7
7
7
9
11
7
13
35
15
200
8
<1
2
5
16
17
18
19
2-CF3
2-OCF3
3-CF3
59
57
17
5
102
33
65
41
11
4
524
127
85
Altogether, from the different analogues prepared, N-
cyclopropylamide 22 featured the most favorable profile, and we
thus decided to characterize this compound further with respect
to functional efficacy in AD related models. In a cellular assay
26
15
7
84
3-OCF3
125
61
76

Table 3. Inhibition of calpain 1, cathepsin selectivity and in-vitro clearance for compounds 5 and 21-26
Cal 1
Ki
[nM]
--- selectivity ratios Cat/Cal ---
mCl*
cytCl*
hu
CatB
23
CatK
22
CatL
15
CatS
>100
rat
<23
hu
27
#
5
P1´
H
39
>70
4
21
22
Et
165
130
55
42
85
74
44
42
60
<23
<23
<23
28
>100
<1
1
23
24
110
70
66
27
88
20
37
130
>100
>100
37
296
>400
>70
5
25
26
48
104
-
70
-
34
-
286
-
>100
>70
3
OCH3
4360
nd
nd
nd
*Units of µL/min/mg. Ranges for human intrinsic cytosolic clearance and qualifiers assigned:
0-14 stable, 14-70 moderate, >70 instable.
Table 4. Inhibition of calpain 1, cathepsin selectivity and in-vitro clearance for compounds 22 and 27-33
Cal 1
Ki
[nM]
*
U
n
i
--- selectivity ratios Cat/Cal ---
mCl*
cytCl*
hu
#
P3
CatB
CatK
CatL
CatS
rat
hu
22 t
s
130
42
-
74
-
42
-
>100
-
<23
<23
28
<1
<1
27
28
H
9700
<23
>70
o
f
73
50
90
18
22
33
93
57
17
>130
>200
>100
>100
>100
>100
<1
<1
>1
µ
L
/
/
29
30
>200
109
>70
>70
m
g
.
162
R
a
n
g
e
31
240
13
>40
>40
>40
>100
>70
nd
s
f
o
r
32
33
545
530
-
-
-
-
-
-
-
-
58
42
2
h
u
m
a
39
27
nd
n
intrinsic cytosolic clearance and qualifiers assigned: 0-14 stable, 14-70 moderate, >70 instable.

using the prevention of NMDA-induced spectrin degradation in
rat hippocampal slice cultures, 22 showed an IC50 value of
385 nM. In addition, in a model of A oligomer- induced
reduction of synaptic transmission in the CA1 area in rat
hippocampal slice cultures, application of 22 completely
prevented the decrease of glutamatergic synaptic strength
(Figure 3).17, 18
Scheme 1 outlines the synthesis of compounds 3–20 in a
general schematic way. The appropriate “P3-P2 acids” employed
as starting material were either commercially available or
prepared according to literature. The synthesis of (2R)-N-(4-
amino-3,4-dioxo-1-phenylbutan-2-yl)-1-benzyl-5-
oxopyrrolidine-2-carboxamide
5
and (2R)-1-benzyl-N-(4-
(cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxo-
pyrrolidine-2-carboxamide 22 is described as example for the
preparation of compounds 4-33. Reductive amination of D-
glutamic acid with benzaldehyde and subsequent cyclisation gave
(R)-1-benzyl-5-oxopyrrolidine-2-carboxylic acid 34. Coupling of
the acid with 3-amino-2-hydroxy-4-phenylbutanamide gave
hydroxyamide 35, which was oxidized to ketoamide 5 using
Pfitzner-Moffat conditions. Alternatively, acid 34 was coupled
with ethyl 3-amino-2-hydroxy-4-phenylbutanoate to give ester
36. Ester cleavage and coupling with cyclopropylamine yielded
hydroxyamide 37, and final oxidation then gave ketoamide 22.
Detailed experimental procedures for the synthesis of 5 and 22 as
key compounds are given in the Supporting Information;
procedures for all other analogues have been reported in
reference 20.
control
Aß oligomer
Aß oligomer+compound 22
6
5
4
3
2
1
0
0
1
2
3
4
5
6
7
Final compounds 4-9 and 11-22 were prepared as 1:1 mixtures
of the corresponding diastereomeres. To address the question of
P1 configuration, we prepared the corresponding R,S and R,R
diastereomers of 22, employing either ethyl (3S)- or (3R)-3-
amino-2-hydroxy-4-phenylbutanoate in the synthesis. Calpain
inhibition was clearly assigned to the R,S-isomer (56 nM vs.
>1000 nM for R;R), confirming our previous results that the P1
S-configuration is favored. However, comparable to what we
found in the nicotinamide series,13 we observed rapid
epimerization at P1 due to the electrophilic group adjacent to the
P1 chiral center (data not shown), and therefore decided to
proceed with the diastereomeric mixtures.
Stimulation itensity (V)
Fig. 3. Compound 22 at 100 nM concentration prevents Aβ
oligomer-induced deficits in synaptic transmission in rat Data
points are shown as mean +/- SEM. The strength of synaptic
transmission is illustrated by the input/output relation in
hippocampal slice cultures after stimulation of the Schaffer
collateral (p=0.016 when compared to untreated oligomer group;
p=0.851 when compared to control.
Scheme 1. Synthetic Route to N-substituted (4-Amino-3,4-dioxo-1-phenylbutan-2-yl)-2-((3-phenyl-1H-pyrazol-1-yl)nicotin¬amides 5
and analoguesa
aReagents and conditions: a) 3-amino-2-hydroxy-4-phenylbutanamide, EDCI, HOBt, triethlyamine, CH2Cl2 or DMF, 0°C – rt. b) EDCI,
dichloroacetic acid, DMSO, rt. c) benzaldehyde, 2N NaOH, then NaBH4, EtOH, rflx. d) ethyl 3-amino-2-hydroxy-4-phenylbutanoate,

EDCI, HOBt, triethlyamine, DMF, 0°C – rt. e) NaOH, MeOH/H2O, rt. f) cyclopropyamine, EDCI, HOBt, triethlyamine, DMF, 0°C – rt.
g) EDCI, dichloroacetic acid, DMSO, rt.
Table 5. Pharmacokinetics of 22 in preclincial species following a single IV or PO dose
IV
PO
species
mouse
dose
2
t1/2
°
AUC0-inf
15.45
CLp
0.13
Vss
1.0
dose
2
t1/2
°
Cmax
2.3
AUC0-inf
F
6.0
6.6
1.7
2.3
5.0
5.1
4.8
1.3
14.46
1.91
1.51
0.22
93.5
rat
dog
2
1
1
1.93
1.82
0.51
1.04
0.61
1.98
3.4
0.6
1.8
2
1
3
0.53
0.98
99.6
83.1
14.3
monkey
0.098
Data provided as mean; ° harmonic mean; Units: Dose (mg/kg); t1/2 (hr); Vss (L/kg); AUC0-inf (µg•hr/mL);
CLp (L/hr•kg); Cmax (µg/mL); Tmax (hr); F (%); IV: intravenous; PO: oral.
Compounds 3-33 were evaluated for inhibition of calpain and the
related most relevant cathepsins B, K, L and S as described
previously.13 In addition, all compounds were routinely examined
for mCl in rat and human liver microsomes and cytosolic stability
screening.
covalent and highly selective calpain inhibitiors. Introduction of
the oxopyrrolidine moiety in P2 led to analogues with high
potency and selectivity such as 5, which was used as lead for
further optimization. However, low stability against carbonyl
reductases resulted in significant cytosolic reduction of the
ketoamide to the corresponding hydroxyamide and therefore
unfavorable cynomolgus PK. Extending P1´ by incorporation of
various aliphatic and aromatic moieties was demonstrated as a
reliable approach to mitigate the metabolic liability of carbonyl
reduction. Unfortunately P1´ extension also led to diminished
calpain inhibition in parallel. Systematic SAR investigations
were undertaken revealing compound 22 (A-1212805) with the
most favorable overall profile balancing calpain potency and
metabolic stability combined with an excellent selectivity. In
preclinical models relevant to AD 22 demonstrated efficacy with
respect to prevention of NMDA-induced neurodegeneration and
A-induced synaptic dysfunction. In addition, oxopyrrolidine 22
demonstrated an excellent safety pharmacology profile and
proceeded to clinical phase I studies as Alicapistat (ABT-957).19
The in vitro ADME profile of compound 22 was characterized
by moderate permeability (Papp Caco-2: 9.4 × 10−6 cm/s). Bi-
directional efflux studies in MDCKII cells demonstrated that 22
is a substrate for P-glycoprotein (efflux ratio: 10.5), but not for
breast cancer resistance protein (efflux ratio: 0.9). Protein
binding was low in human plasma with unbound fraction of
approximately 0.3. 22 had good liver microsomal and hepatocyte
stability across rat, dog, monkey, and human. As compared to the
P1´ un-substituted ketoamides 22 also displayed a much
improved liver cytosolic stability in human and monkey
indicating a significant improvement on metabolic liability of
carbonyl reduction. This was supported by non-detectable level
of hydroxyamide metabolite in both human and monkey
hepatocytes. An in vitro metabolism study using [3H]-labeled 22
suggested that metabolism primarily occurred at the N-benzyl
oxopyrrolidine moiety via N-debenzylation, whereas carbonyl
reduction to form hydroxyamide metabolite was a minor
metabolic pathway. CYP phenotyping studies suggested that
CYP3A4 and 3A5 were the primary CYP isoforms for
metabolism.
Notes
A. M. and Y. L. are former AbbVie employees.
Current affiliation: Y. Lao: Eli Lilly and Company; Lilly
Corporate Center, Indianapolis IN 46285 U.S. V. Nimmrich:
AbbVie Deutschland GmbH & Co. KG, Development Sciences,
Knollstrasse, 67061 Ludwigshafen, Germany.
The pharmacokinetic behavior of 22 was evaluated in CD-1
mice, Sprague−Dawley rats, beagle dogs, and cynomolgus
monkeys (Table 5). The pharmacokinetic profile was
characterized by low to moderate mean plasma clearance values
(CLp) in mouse, rat, and dog (0.13-1.04 L/hr•kg), while high in
monkey (1.98 L/hr•kg). Mean steady-state volume of distribution
values (Vss) were moderate in mouse, dog, and monkey (0.64-1.8
L/kg), but higher in rat (3.4 L/kg). The plasma elimination half-
life (t1/2) was shortest in dog (1.7 hours), followed by 2.3 hours in
monkey and approximately 6.0 hours in mouse and rat. Oral
bioavailability (F) values were high in mouse, rat, and dog
(>80%), while moderate in monkey (14%). In contrast to
compound 5 with 0% oral bioavailability, 22 displayed an
improved oral bioavailability in monkey, consistent with the
enhanced liver cytosolic stability to minimize the carbonyl
reduction. Moderate oral bioavailability and high Clp value in
monkey could be attributed to the first pass metabolism by
CYP3A enzymes. 22 partitioned into the rat brain with unbound
brain to plasma AUC ratio of 0.25.
This study was sponsored by AbbVie. AbbVie contributed to
the study design, research, and interpretation of data, writing,
reviewing, and approving the manuscript. The authors declare the
following competing financial inter-est(s): The authors are
current or former employees of AbbVie (or Abbott Laboratories
prior to separation), and may own company stock.
Acknowledgments
We thank the global AbbVie calpain project team, in
particular the Ludwigshafen synthesis, analytics and ADME
teams as well as the Lake County ADME team for metabolism
studies.
Appendix A. Supplementary Data
Supplementary data to this article can be found online at
LINK
In summary, we established ketoamide-based 1-benzyl-5-
oxopyrrolidine-2-carboxamides as a novel series of reversible,

Abbreviations
ADME, absorption, distribution, metabolism, excretion; Cal,
calpain; Cat, cathepsin; cyno, cynomolgus monkey; cytCl,
cytosolic
clearance;
EDCI,
1-ethyl-3-(3-dimethylamino-
propyl)carbodiimide; F, bioavailability; HOBt, hydroxyl-
benzotriazole; mCl, microsomal clearance; Papp, apparent
permeability; PK, pharmacokinetics.
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Graphical Abstract
Discovery of ABT-957: 1-Benzyl-5-oxo-
pyrrolidine-2-carboxamides as selective
calpain inhibitors with enhanced metabolic
stability
Leave this area blank for abstract info
Katja Jantos, Andreas Kling, Helmut Mack, Wilfried Hornberger, Achim Moeller, Volker Nimmrich,
Yanbin Lao , Marjoleen Nijsen
O
O
. Highly selective vs. related
cystein protease cathepsins
N
N
H
H
N
O
. Enhanced stability vs.
carbonyl reduction
O
A-1212805
ABT-957