Mitigating the Metabolic Liability of Carbonyl Reduction: Novel Calpain Inhibitors with P1′ Extension

Article abstract of DOI:10.1021/acsmedchemlett.7b00494

Dysregulation of calpains 1 and 2 has been implicated in a variety of pathological disorders including ischemia/reperfusion injuries, kidney diseases, cataract formation, and neurodegenerative diseases such as Alzheimer's disease (AD). 2-(3-Phenyl-1H)-pyrazol-1-yl)nicotinamides represent a series of novel and potent calpain inhibitors with high selectivity and in vivo efficacy. However, carbonyl reduction leading to the formation of the inactive hydroxyamide was identified as major metabolic liability in monkey and human, a pathway not reflected by routine absorption, distribution, metabolism, and excretion (ADME) assays. Using cytosolic clearance as a tailored in vitro ADME assay coupled with in vitro hepatocyte metabolism enabled the identification of analogues with enhanced stability against carbonyl reduction. These efforts led to the identification of P1′ modified calpain inhibitors with significantly improved pharmacokinetic profile including P1′ N-methoxyamide 23 as potential candidate compound for non-central nervous system indications.

Full text of DOI:10.1021/acsmedchemlett.7b00494

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Letter
Mitigating the Metabolic Liability of Carbonyl Reduction
– Novel Calpain Inhibitors with P1´ Extension
Andreas Kling, Katja Jantos, Helmut Mack, Wilfried Hornberger, Gisela Backfisch,
Yanbin Lao, Marjoleen Nijsen, Beatrice Rendenbach-Mueller, and Achim Moeller
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00494 • Publication Date (Web): 04 Feb 2018
Downloaded from http://pubs.acs.org on February 8, 2018
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Mitigating the Metabolic Liability of Carbonyl Reduction – Novel
Calpain Inhibitors with P1´ Extension
Andreas Kling, †,* Katja Jantos, † Helmut Mack, † Wilfried Hornberger, † Gisela Backfisch, ‡ Yanbin Lao,
⊥,#,¥ Marjoleen Nijsen, ⊥ Beatrice Rendenbach-Mueller, § Achim Moeller †,#
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† AbbVie Deutschland GmbH & Co. KG, Neuroscience Research, Knollstrasse, 67061 Ludwigshafen, Germany
‡ AbbVie Deutschland GmbH & Co. KG, Development Sciences, Knollstrasse, 67061 Ludwigshafen, Germany
⊥ AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064-6125, United States
§ AbbVie Deutschland GmbH & Co. KG, Neuroscience Development, Knollstrasse, 67061 Ludwigshafen, Germany
KEYWORDS: Calpain inhibitor, carbonyl reduction, cytosolic stability, cathepsin selectivity.
ABSTRACT: Dysregulation of calpains 1 and 2 has been implicated in a variety of pathological disorders including ische-
mia/reperfusion injuries, kidney diseases, cataract formation, and neurodegenerative diseases such as Alzheimer´s disease (AD).
2-(3-Phenyl-1H)-pyrazol-1-yl)nicotinamides represent a series of novel and potent calpain inhibitors with high selectivity and in
vivo efficacy. However, carbonyl reduction leading to the formation of the inactive hydroxyamide was identified as major meta-
bolic liability in monkey and human, a pathway not reflected by routine ADME assays. Using cytosolic clearance as a tailored in
vitro ADME assay coupled with in vitro hepatocyte metabolism enabled the identification of analogues with enhanced stability
against carbonyl reduction. These efforts led to the identification of P1´ modified calpain inhibitors with significantly improved
pharmacokinetic profile including P1´ N-methoxyamide 23 as potential candidate compound for non-CNS indications.
The calpains are a family of Ca2+-dependent intracellular cysteine
proteases that proteolyze a wide variety of cytoskeletal, mem-
brane-associated and regulatory proteins.1 Calpains regulate the
function and metabolism of proteins which are key to the patho-
genesis of several human diseases.2 In particular, calpain 1 and 2
have been shown to be involved in acute and chronic pathologi-
cal processes such as ischemia/reperfusion injury, traumatic
brain injury (TBI), Alzheimer´s disease (AD), and Multiple Sclero-
Figure 1: General structure of ketoamide-based calpain inhibitors
sis (MS). Furthermore, inhibition of calpains is known to exert
showing the essential pharmacophores required for activity and
general cell- and organo-protective effects after a pathological
insult. Therefore, calpain has been proposed as an attractive
selectivity.
target for diseases such as chronic kidney disease, myocardial
Recently we reported on 2-(3-phenyl-1H-pyrazol-1-yl)-
infarction, cataract formation, and neurological disorders such as
nicotinamides as highly potent and selective inhibitors of cal-
AD or TBI.3,4
pain.9 In particular, N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-
(3-phenyl-1H-pyrazol-1-yl)nicotinamide 1 (A-933548) and its 4-
fluoro analogue N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-
The majority of calpain inhibitors described so far are active site
directed reversible inhibitors with a structure built in a modular
concept (Figure 1). An electrophilic group, typically a ketoamide
or a (masked) aldehyde, is required for covalent interaction with
the active cysteine thiol, while the residues on the adjacent sides
of this warhead interact with pockets at the subsites of calpain in
a manner similar to substrate binding (for a more detailed de-
scription of protease substrate designation see lit 5). A variety of
potent nonpeptidic calpain inhibitors has been reported, howev-
er none of these compounds was advanced into clinical devel-
opment, either due to lack of selectivity and/or unfavorable PK
properties.6-8
(4-fluorophenyl)-1H-pyrazol-1-yl)nicotinamide
2
(A-953227)
feature enhanced selectivity versus related cysteine protease
cathepsins, favorable microsomal stability, and efficacy in cellular
assays (Figure 2). In addition, we demonstrated that compound 2
was efficacious in a set of AD related models, and had an overall
favorable safety profile.9
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based on liver cytosolic stability as a tailored assay, coupled with
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other tier 1 in vitro ADME assays. Compounds with improved
cytosolic stability were evaluated for hydroxyamide metabolite
formation in monkey and human hepatocytes, followed by mon-
key PK to assess in vivo carbonyl reduction with PK parameters
(CL, t1/2 and oral F). In addition, in vivo metabolite formation was
determined. Herein we describe the synthesis and characteriza-
tion of novel calpain inhibitors with P1´ extension as means to
enhance stability versus carbonyl reduction. From a set of differ-
ent analogues prepared in this series, cyclopropyl and O-methyl
were identified as most favorable P1´ moieties balancing calpain
inhibition, selectivity and overall metabolic stability, also showing
an improved PK profile across preclinical species.
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Figure 2: Structure and calpain inhibition of compounds 1 and 2.
However, further ADME and pharmacokinetic profiling (PK)
revealed significant species differences in metabolism. Whereas
in rodents ketoamides 1 and 2 are mainly hydrolyzed to the
corresponding ketoacid and then oxidized to give the homolo-
gous acids, non-CYP mediated carbonyl reduction to the hydrox-
yamide was identified as the major metabolic pathway in cyno-
molgus monkey and human (Figure 3).
Cytosolic Stability: Intrinsic cytosolic clearance (cytClint) was
implemented as tailored in vitro ADME assay to screen for com-
pounds with enhanced stability against reductases. In this assay
we measured the percentage of parent compound lost over time
in cytosolic incubations, and used this data to calculate intrinsic
clearance (see Supporting Information). Clearance ranges were
adjusted to hepatic plasma flow of human and monkey in analo-
gy to mClint, with the following qualifiers assigned to evaluate
cytosolic stability of a compound (Table 1).
Table 1. Ranges for Intrinsic Cytosolic Clearance (cytClint)
and Qualifiers Assigned
cyno
hu
qualifier
stable
[µL/min/mg]
[µL/min/mg]
0 - 18
0 - 14
14 – 70
> 70
Figure 3: Species specific metabolism of compound 2. Hydroxy-
amide 3 and acid 4 are inactive (Ki values > 10.000 nM).
moderate
instable
18 – 90
> 90
In general, carbonyl reduction is mediated by multiple cytosolic
reductases, most of them belonging to the superfamilies of
NADPH-dependent short-chain dehydrogenases/reductases and
aldo-keto reductases. These enzymes are ubiquitous, found in
many tissues including liver, lung, brain, kidney and blood, and
show broad and overlapping substrate specificities. Differences
in multiplicity and tissue distribution can cause specific cellular
metabolism for carbonyl-containing compounds and hence dif-
ferent metabolic pathways across species.10, 11 Further investiga-
tion of compound 2 suggested that the carbonyl reductase activi-
ties impacting the ketoamide moiety were cytosolic and NADPH-
dependent. Preclinical PK studies with 2 were consistent with
data from in vitro metabolism, demonstrating good to moderate
bioavailability (F) in rat and dog (F = 68% and 30%, respectively),
but low bioavailability in monkey (F = 4.5%).9 Significant for-
mation of the hydroxyamide metabolite was observed in mon-
key, with the hydroxyamide present in 82 fold excess compared
to parent compound, while less was formed in rat and dog (2.3
and 0.5 fold, respectively – based on AUC). Consistently, data
from a first-in-human Phase 1 study testing single doses up to
800 mg showed that compound 2 had low bioavailability (Fe ~
10%), short effective half-life (t1/2), and significant formation of
the hydroxyamide metabolite (95 fold excess of hydroxyamide
metabolite to parent).
In Vitro Metabolite/Parent Ratio in Hepatocytes: As stated
above, enhanced cytosolic stability is supposed to translate into
decreased formation of hydroxyamide metabolites in human and
monkey hepatocytes, which should be reflected by a change in
the ratio of hydroxyamide metabolite to the corresponding par-
ent compound. Thus, the metabolite to parent ratio (M/P ratio)
was determined as an additional parameter for a set of advanced
compounds (see Supporting Information).
Table 2. Intrinsic Cytosolic Stability (cytClint) and Metabolite
to Parent Ratio (M/P) in Hepatocytes for Compound 2
cytCl*
cyno
39
M/P ratio
compd
2
hu
cyno
3.4
hu
> 70
8.0
* [µL/min/mg]
On the basis of these results our goal was to identify calpain
inhibitors with enhanced stability against carbonyl reduction,
which should translate into an improved PK profile in humans.
Carbonyl reduction as metabolic liability is not reflected by
standard in vitro stability assays, such as intrinsic liver microso-
mal clearance (mClint), which is routinely employed during lead
optimization. Hence we have developed a new screening assay
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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 9 and analogues a
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aReagents and conditions: a) ethyl (2S*,3R*)-3-amino-2-hydroxy-4-phenylbutanoate hydrochloride, EDCI, HOBt, triethlyamine, CH2Cl2,
5°C – rt.; b) LiOH, THF/H2O, 10°C - rt.; c) cyclopropylamine, EDCI, HOBt, triethlyamine, CH2Cl2, 5°C – rt.; d) EDCI, dichloroacetic acid,
DMSO, rt.
Table 2 depicts cytClint and M/P ratios obtained for compound 2.
CytCl is moderate in cynomolgus monkey and high in human,
which correlates well with the M/P ratios observed. The data also
agree with the PK in these species (see Table 5), clearly reflecting
the liability for carbonyl reduction.
Synthesis and Screening: Scheme 1 outlines the synthesis of
cyclopropyl
2-hydroxy-4-phenyl-3-(2-(3-phenyl-1H-pyrazol-1-
yl)nicotinamido)butanoate 15 as a general example for the syn-
thesis of compounds 9 – 32 comprising different P1´ moieties.
Starting from 2-(3-phenyl-1H-pyrazol-1-yl)nicotinic acid 5, cou-
pling with ethyl (2S*,3R*)-3-amino-2-hydroxy-4-phenylbutanoate
gave (2S*,3R*)-2-hydroxy-4-phenyl-3-((2-(3-phenyl-1H-pyrazol-1-
yl)pyridin-3-yl)amino)butanoic acid 6. Ester cleavage and cou-
pling of acid 7 with cyclopropylamine yielded hydroxyamide 8.
Final oxidation using either Pfitzner-Moffat conditions12 or, in the
case of alkoxy-substituted amides, 2-iodobenzoic acid13 gave
ketoamides 9 – 32 as racemic mixtures.14,15 Detailed experi-
mental procedures for the preparation of key compounds 15 and
23 are given in the Supporting Information.
Compounds 9 - 32 were evaluated for enzyme inhibition using
kinetic fluorescence assays as described in lit. 9 (selectivity data
only shown for selected compounds). In addition, all compounds
were routinely submitted to tier 1 mCl in rat and human hepato-
cytes and cytosolic stability screening (Tables 3 and 4).
SAR of P1´ Modification: Ethylamide 9 had been prepared during
our efforts to investigate the SAR around 2-(3-phenyl-1H)-
pyrazol-1-yl)nicotinamides such as 1 and 2. Interestingly, alt-
hough showing significantly reduction in calpain inhibition, 9
displayed good cytosolic stability and low M/P ratios (0.5 for
cyno and 0.2 for human, respectively), which prompted us to
examine the SAR for the P1´ position more thoroughly. Previous
efforts had shown that the presence of the P1´ amide NH is
essential for calpain inhibition, therefore tertiary amides were
not included. Due to the better calpain inhibition, compound 1
was used as starting point for optimization. Altogether, about 80
analogues with different P1´ extensions were prepared, including
a set of different alkyl-, O-alkyl-, aryl-, and hetaryl residues. Se-
lected examples are depicted in Tables 3 and 4 (selectivity versus
related cysteine protease cathepsins shown in the Supporting
Information).
mCl*
cytCl*
cyno
Cal 1
Ki [nM]
compd
R
rat
22
hu
6
hu
40
>70
28
21
12
4
1
2
-
-
18
34
74
39
16
12
4
15
23
9
Et
CH3
6908
380
480
2600
45
>70
18
10
11
24
>100
81
64
49
5
12
13
14
15
470
950
205
>100
53
>70
37
8
6
5
8
4
64
27
12
490
1350
550
>100
nd
>70
nd
52
8
7
8
9
9
4
16
17
18
>100
81
7
>5000
24
10
19
110
>100
>70
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19
20
21
330
210
>100
>100
>70
>70
38
11
11
16
22
* [µL/min/mg]
Table 3. Inhibition of Calpain 1 and Microsomal and Cyto-
solic Stability of Compounds 1,
2
and
9 – 22
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Table 5. Pharmacokinetics of Compounds 1, 2, 15 and 23 in Cynomolgus Monkeys Following a Single IV or PO Dose
1
IV
PO
2
3
4
5
6
7
8
9
compd
Dose
t1/2
1.1
1.1
1.4
7.8
°
AUC0-inf
CLp
1.5
2.0
3.0
1.4
Vss
1.1
1.8
6.8
9.6
Dose
1
t1/2
-
°
Cmax
-
tmax
-
AUC0-inf
F
-0
M/PAUC
nd
1
2
1
1
1
1
660
520
370
740
-
10
3
6.3
7.5
7.4
0.02
9.3
276
13.3
1.3
2.5
230
75
4.5
6.8
58.9
82.4
0.9
15
23
3
1310
0.04
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Data provided as mean; ° harmonic mean; Units: Dose (mg/kg); t1/2 (hr); Vss (L/kg); AUC0-inf (ng•h/mL); CLp (L/h•kg); Cmax (ng/mL); tmax
(h); F (%); IV: intravenous; PO: oral. M/PAUC: AUC ratio of hydroxyamide metabolite to parent.
inhibition. Results for compounds 20 - 22 suggest that, in terms
of calpain inhibition, an aromatic moiety in P1´ is better tolerat-
ed. However, these analogues were not suitable for further
advancement due to insufficient stability in liver microsomes
(mCl > 70 and 100 µL/min/mg, respectively), probably due to the
enhanced lipophilicity in P1´. In the case of P1´ N-alkoxy ana-
logues 23 – 32, we again observed a significant improvement in
stability versus carbonyl reduction (Table 4). In this subseries the
negative impact of P1´ extension on calpain inhibiton was less
pronounced: in general the P1´ N-alkoxy amides were more
potent than the corresponding N-alkyl analogues. Compounds 23
– 26 and 28 – 30 showed Ki values for calpain in the range of 75
to 150 nM, which is 4 to 7 fold reduction in calpain inhibition
compared to 1. The P1´ comprising amine analogues 31 and 32
did not show any remarkable properties. Although displaying the
highest calpain potency in this series, compounds 24, 25, and 28
did not fulfill our criteria for cathepsin selectivity (Supporting
Information), and thus were not advanced.
Altogether, from the different amides prepared in this effort,
cycloalkyl amide 15 and N-methoxy amide 23 displayed the best
balance between calpain inhibition, microsomal and cytosolic
stability, and selectivity versus cysteine protease cathepsins. To
determine cellular efficacy, cpds. 15 and 23 were examined in a
functional tissue assay using the prevention of NMDA-induced
intracellular spectrin cleavage in rat hippocampal slice cultures as
read-out.16, 17 Although featuring diminished calpain inhibition in
vitro, cellular efficacy was in a range comparable to primary
amide 1 with compounds 15 and 23 showing IC50 values of 750
nM and 2150 nM, respectively. For both compounds enhanced
cytosolic stability was reflected by reduced hydroxyamide me-
tabolite formation in hepatocytes with M/P ratios of < 0.1 (cyno)
and 0.2 (hu) for 15, and < 0.1 (cyno, hu) for 23, respectively.
ADME and Monkey PK: To determine whether the improvement
in in vitro metabolic stability is translated to the in vivo situation,
we advanced both compounds to further profiling in monkey PK,
using primary ketoamide 1 as reference. In vivo monkey pharma-
cokinetic behavior of compounds 1, 2, 15 and 23 are summarized
in Table 5. Consistent with in vitro metabolism, 23 demonstrated
a significant reduction in the formation of the hydroxyamide
metabolite and improved monkey PK profile: low clearance, long
half-life, and high oral bioavailability. Despite good cytosolic
stability and low M/P ratio in cynomolgus monkey hepatocytes,
compound 15 showed suboptimal in vivo monkey PK, which
could be explained by increased Cyp-mediated clearance ob-
served in liver microsomes for 15 compared to 23 (39 versus < 23
µL/min/mg).
Table 4. Inhibition of Calpain 1 and Microsomal and Cyto-
solic Stability of Compounds 1,
2
and 23 – 32
mCl*
cytCl*
cyno hu
74
Cal 1
Ki [nM]
compd
R
rat
22
15
21
32
96
hu
1
H
18
34
6
40
>70
2
2
-
23
11
10
20
39
1
23
24
25
CH3
Et
120
110
75
<1
<1
29
<1
2
220
>100 >70
33
26
27
28
185
90
44
78
11
17
1
2
<1
8
150
120
59
15
21
3
1
3
4
29
>100
30
31
1060
265
12
17
9
6
3
2
2
<1
32
* [µL/min/mg]
In general, in comparison to compound 1, analogues with P1´ N-
alkyl extension (Table 3) showed a robust enhancement in cyto-
solic stability, which might be attributed to the inability of car-
bonyl reductases to adapt to P1´ extended ketoamides as sub-
strates. However, in parallel we also observed a significant reduc-
tion in calpain inhibition.
The most potent compound in this subseries was benzylamide 20
with a Ki of 108 nM showing“only” 6 fold reduction in calpain
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Conclusion: Our goal was to identify calpain inhibitors with en-
The authors declare the following competing financial interest(s):
The authors are current or former employees of AbbVie (or
Abbott Laboratories prior to separation), and may own company
stock.
1
2
3
4
5
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7
8
hanced stability versus carbonyl reduction. Based on the results
obtained for compound 2, we developed cytosolic clearance as in
vitro ADME assay reflecting carbonyl reduction as metabolic
liability. In addition, we confirmed that compounds with good
cytosolic stability showed significant reduction in formation of
hydroxyamide metabolites in vitro and in vivo. CytCl and hepato-
cyte M/P ratio were then used routinely as tailored in vitro ADME
assays in our screening funnel. Starting from ethyl amide 9 as
lead, we identified P1´ extension as reliable approach to address
carbonyl reduction as metabolic liability. Incorporation of differ-
ent P1´ moieties led to a robust enhancement of cytosolic stabil-
ity in our lead series, although this modification also resulted in
diminished calpain inhibition. Systematic investigation of the SAR
in P1´ revealed that the corresponding cyclopropyl and N-
methoxy amides 15 and 23 showed the best balance between
calpain potency, cathepsin selectivity and overall ADME proper-
ties. Further profiling in preclinical PK studies showed improved
PK profiles, in particular for compound 23.
ACKNOWLEDGMENT
We thank the global Abbott/AbbVie calpain project team, in
particular A. Boehler, J. Froggett, S. Heitz, S. Maurus, M. Mitgude,
V. Ott and C. Thiem for synthesis, C. Krack and the LU team from
NC for analytical support, S. Biesinger, S. Koller, P. Göck-Sturm, S.
Kiess, G. Sauer for screening, the LU ADME team and M.
Michmerhuizen and X. Li for metabolism studies
Design, study conduct, and financial support for this research
was provided by AbbVie. AbbVie participated in the interpreta-
tion of data, review, and approval of the publication.
9
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In conclusion, N-(4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-
yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide 23 represents the
most favorable analogue from this series combining enhanced
metabolic stability, good potency against calpain, selectivity
versus related cysteine protease cathepsins, in particular cathep-
sins L and S, and favorable PK with good oral bioavailabilities
across pre-clinical species. The brain to plasma drug concentra-
tion of < 0.05 in rat suggests that compound 23 does not pene-
trate into the brain and is peripherally restricted. In addition, N-
methoxy amide 23 did not show cross-reactivity in the standard
receptor and enzyme panels (CEREP and MDS Enzyme Profiling
Screen, up to 10 µM concentration), or any liability in hERG, and
rat cardiovascular safety (data not shown). Based on these re-
sults, compound 23 might have potential as candidate calpain
inhibitor for non-CNS indications like kidney diseases, ische-
mia/reperfusion injury, and cataract.
ABBREVIATIONS
ABBREVIATIONS
ADME, absorption, distribution, metabolism, excretion; Cal,
calpain; Cat, cathepsin; cyno, cynomolgus monkey; cytCl, cyto-
solic
dimethylaminopropyl)carbodiimide; Fe, estimated bioavailability;
HATU, [O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-
clearance;
EDCI,
1-ethyl-3-(3-
tetramethyluroniumhexafluorphosphat]; hERG, human Ether-à-
go-go-Related Gene; HOBt, hydroxybenzotriazole; mCl, microso-
mal clearance; PK, pharmacokinetics.
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Trends Mol. Med. 2001, 7, 355-362.
ASSOCIATED CONTENT
Supporting Information
3
Ono, Y.; Saido, T. C.; Sorimachi, H.; Calpain Research for Drug
Discovery: Challenges and Potential. Nat. Rev. Drug Discovery 2016,
854-876.
The Supporting Information is available free of charge on the ACS
Publications website.
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Experimental procedures for the preparation of compounds 15
and 23; selectivity of compounds 1, 2 and 9 - 32 versus related
cysteine protease cathepsins B, K, L, and S; determination of
intrinsic cytosolic stability in cynomolgus monkey and human
liver cytosol; determination of hydroxyamide metabolite parent
ratio in cynomolgus monkey and human hepatocytes; pharmaco-
kinetic behaviour and determination of hydroxyamide metabolite
1
parent ratio in cynomolgus monkey; H NMR and 13C spectra for
compounds 15 and 23.
8 Low, K. E.; Ler, S.; Chen, K. J.; Campbell, R. L.; Hickey, J. L.; Tan, J.;
Scully, C. C. G.; Davies, P. L.; Yudin, A. K.; Zaretsky, S. Rational Design
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AUTHOR INFORMATION
Corresponding Author
* Phone: +49(0)621-5893449;
E-mail: andreas.kling@abbvie.com
9
Kling, A.; Jantos, K.; Mack, H.; Hornberger, W.; Drescher, K.;
Nimmrich, V.; Relo, A.; Wicke, K.; Hutchins; C. W.; Lao, Y.; Marsh, K.;
Moeller, A. Discovery of Novel and Highly Selective Inhibitors of
Calpain for the Treatment of Alzheimer´s Disease: 2-(3-Phenyl-1H-
pyrazol-1-yl)-nicotinamides. J. Med. Chem. 2017, 60, 7123-7138.
10 Hoffmann, F.; Maser, E. Carbonyl Reductases and Pluripotent
Hydroxysteroid Dehydrogenases of the Short-Chain Dehydrogenas-
es/Reductases Superfamily. Drug Metab. Rev. 2007, 39, 87-144.
Present Addresses
¥ For Y. L.: Eli Lilly and Company; Lilly Corporate Center, Indian-
apolis IN 46285 U.S.
Notes
# A. M. and Y. L. are former AbbVie employees.
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