Thiophene-Pyrazolourea Derivatives as Potent, Orally Bioavailable, and Isoform-Selective JNK3 Inhibitors

Article abstract of DOI:10.1021/acsmedchemlett.0c00533

Potent JNK3 isoform selective inhibitors were developed from a thiophenyl-pyrazolourea scaffold. Through structure activity relationship (SAR) studies utilizing enzymatic and cell-based assays, and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies, potent and highly selective JNK3 inhibitors with oral bioavailability and brain penetrant capability were developed. Inhibitor 17 was a potent and isoform selective JNK3 inhibitor (IC50 = 35 nM), had significant inhibition to only JNK3 in a panel profiling of 374 wild-type kinases, had high potency in functional cell-based assays, had high stability in human liver microsome (t1/2 = 66 min) and a clean CYP-450 inhibition profile, and was orally bioavailable and brain penetrant. Moreover, cocrystal structures of compounds 17 and 27 in human JNK3 were solved at 1.84 ?, which showed that these JNK3 isoform selective inhibitors bound to the ATP pocket, had interactions in both hydrophobic pocket-I and hydrophobic pocket-II.

Full text of DOI:10.1021/acsmedchemlett.0c00533

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Featured Letter
Thiophene-Pyrazolourea Derivatives as Potent, Orally Bioavailable,
and Isoform-Selective JNK3 Inhibitors
Yangbo Feng,* HaJeung Park, Luke Bauer, Jae Cheon Ryu, and Sung OK Yoon*
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sı Supporting Information
ABSTRACT: Potent JNK3 isoform selective inhibitors were
developed from a thiophenyl-pyrazolourea scaffold. Through
structure activity relationship (SAR) studies utilizing enzymatic
and cell-based assays, and in vitro and in vivo drug metabolism and
pharmacokinetic (DMPK) studies, potent and highly selective
JNK3 inhibitors with oral bioavailability and brain penetrant
capability were developed. Inhibitor 17 was a potent and isoform
selective JNK3 inhibitor (IC = 35 nM), had significant inhibition
50
to only JNK3 in a panel profiling of 374 wild-type kinases, had high
potency in functional cell-based assays, had high stability in human liver microsome (t1/2 = 66 min) and a clean CYP-450 inhibition
profile, and was orally bioavailable and brain penetrant. Moreover, cocrystal structures of compounds 17 and 27 in human JNK3
were solved at 1.84 Å, which showed that these JNK3 isoform selective inhibitors bound to the ATP pocket, had interactions in both
hydrophobic pocket-I and hydrophobic pocket-II.
KEYWORDS: JNK3, Kinase Inhibitor, Alzheimer’s Diseases (AD), Pyrazolourea, Neurodegeneration
here are three isoforms for the mitogen-activated protein
T
kinase c-Jun N-terminal kinases: JNK1, JNK2, and
1
JNK3. Among them, JNK1 and JNK2 are ubiquitously
2
,3
expressed, while JNK3 is mainly expressed in the central
1
,2
nervous system (CNS). JNK3 has been found to be related
to various CNS and/or neurodegenerative diseases, such as
4
−7
8−10
Alzheimer’s disease (AD),1
Parkinson’s disease (PD),
12,13 14
1
Huntington disease (HD),1 stroke,
epilepsy, and spinal
5
muscular atrophy (SMA). Therefore, development of brain
penetrant and potent JNK3 inhibitors has been the focus of
many academic laboratories and pharma over the past
Figure 1. Two lead structures from the pyrazole-urea scaffold and
strategies for further optimizations.
1
6−25
decades.
In addition, since JNK1 is found to be not
obviously related to neurodegenerative diseases, identification
and development of isoform selective JNK3 inhibitors are of
particular interest for drug discovery. Despite numerous efforts
to develop JNK3 inhibitors, so far none of the small molecule
JNK3 compounds have entered clinical trials. Therefore, novel
JNK3 inhibitors with excellent DMPK properties are still
needed for CNS applications.
inhibitions and also gave fair PK properties by iv dosing. In
addition, 1 demonstrated fair brain penetration in mice.
16
The favored properties encouraged us to carry out further
optimizations for this pyrazole-urea scaffold in order to obtain
better JNK3 inhibitors for CNS applications. The major
liability was the low oral bioavailability; compounds we
previously reported gave none or very low oral bioavailability.
In addition, the general in vivo PK properties also needed to be
In our previous studies, we discovered that compounds
derived from a pyrazole-urea scaffold could yield potent and
isoform selective JNK3 inhibitors, as exemplified by com-
16
improved.
16
pounds 1 and 2 in Figure 1. These JNK3 inhibitors had high
selectivity against JNK1 and the closely related kinase p38α.
Compound 2 even had high selectivity against JNK2 (>500-
Received: October 6, 2020
Accepted: November 30, 2020
1
6
fold). Compounds from this scaffold also possessed high
general kinase selectivity. In a panel profiling study against a
panel size of 464 kinases, at 10 μM, 1 showed significant
inhibition (>80% inh.) to only 4 off-targets (Clk2, haspin,
Mek3, and Ysk4). Both inhibitors 1 and 2 were clean in P450
©
XXXX American Chemical Society
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A
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To obtain JNK3 inhibitors having higher drugability for
CNS applications, our optimizations will focus on two areas, as
shown in Figure 1: the left-side N-phenyl amide group (Area-
A) and the right-side aniline phenyl moiety (Area-B). Based on
was applied (analogue 6), which exhibited a JNK3 inhibition
IC of 0.05 μM and had high isoform selectivity against JNK1
5
0
(IC : 3.6 μM, 72-fold selectivity). Moreover, both 5 and 6 had
5
0
almost no inhibitions to their closely related kinase p38α (IC50
> 20 μM). Therefore, the chemotype incorporating a 3,5-
disubstituted thiophene ring (as in 6) will be used for further
optimizations.
16
the cocrystal structure of 2 in JNK3, small substitutions (R1)
other than the 2-Cl) to the aniline phenyl group (Area-B)
(
could be tolerated. We reasoned that substitutions by electron-
withdrawing groups might be able to improve PK properties
and reduce potential metabolic toxicity. Our previous SAR
studies demonstrated that the left-side amide NH moiety is
indispensable for a high JNK3 affinity. Based on the crystal
structure of 2 in JNK3, the phenyl ring of the benzamide
provided hydrophobic interactions with surrounding protein
residues and thus could be replaced by other aromatic
structures without significantly affecting the JNK3 inhibition
activity.
We then attempted to optimize the amide moiety in
compound 6. As shown in Table 1, various amides were
prepared to optimize the JNK3 inhibitory potency and isoform
selectivity against JNK1 and JNK2 (assessed by the ratio of the
IC50 value of JNK1 or JNK2 over JNK3). In terms of JNK3
inhibitory activity, simple alkyl amides (7 and 8) resulted in a
reduction of JNK3 inhibition compared to the heterocyclic
ring-containing amide 6. Replacing the azetidine with an R-
configured pyrrolidine (9) also reduced the JNK3 inhibition.
N-Methylation to the ring-nitrogen (10) gained some activity.
Interestingly, deuteration to the N-methyl group (11) did not
affect the activity at all. On the other hand, changing the
chirality of the pyrrolidine ring from R to S (12) led to an
increase in JNK3 inhibitory activity. Moreover, application of a
bulkier N-substitution (13) further increased the JNK3
inhibition. Further increasing the ring size led to a slight
decrease in JNK3 inhibition (14 vs 12). However, replacing
the ring nitrogen with an oxygen (15) could gain JNK3
inhibitory activity. In addition, replacing the 2H-pyran in 15 by
a tetrahydrofuran ring (16) led to a compound with a very
high JNK3 inhibitory activity (IC : 8 nM). Further decreasing
We herein report the SAR optimizations based on these two
areas of lead compounds 1 and 2. Highly potent and selective
(
including isoform selectivity against JNK1) JNK3 inhibitors
were obtained from the optimizations. In addition, the
optimized novel JNK3 inhibitors exhibited oral bioavailability
and good brain penetration. The synthesis, purification, and
characterization of all JNK3 inhibitors (analogues 3−28) were
following similar procedures as those described in our previous
publication (also see the Supporting Information).
The first step in our optimizations was to replace the phenyl
ring in Area-A with a 5-membered aromatic moiety. We started
by using a thiazole ring. As shown in Figure 2, the thiazole
5
0
the ring size by applying an oxetane moiety (17) resulted in
some loss of JNK3 inhibitory activity, but the IC50 of 17 was
still comparable to or slightly better than that of lead 6.
Interestingly, α-methyl substitution to the oxetane ring (18)
did not significantly affect the JNK3 inhibition. Insertion of a
methylene group between the heterocyclic ring and the amine
moiety (compounds 19 to 24) led to deteriorated JNK3
inhibitors. Generally, these compounds had lower JNK3
inhibitions as compared to their corresponding analogues,
such as 19 vs 14, 21 vs 12, and 22 vs 16. The only exception is
compound 24. Its IC50 value was about half that of its
corresponding analogue 15.
Similar to lead inhibitors 5 and 6, the IC50 values against
p38α for compounds listed in Table 1 were all greater than 20
μM, indicating a generally excellent selectivity of this pyrazole-
urea based scaffold against kinase p38α (the selectivity for
most compounds is >100-fold). Ιn terms of the isoform
selectivity against JNK1, some compounds showed a fair
selectivity (R value between 20 and 50), such as compounds 9,
1
4, 15, and 19−22; many compounds exhibited a good
selectivity (R value between 50 and 100), such as compounds
, 8, 10−14, 18, and 24; and a few compounds demonstrated
Figure 2. Optimization of Area-A: replacement of the benzamide
phenyl ring by a 5-membered aromatic moiety.
6
an excellent selectivity (R value greater than 100), such as
compounds 7, 16, 17, and 23. In summary, amides with a
nitrogen-containing heterocyclic ring gave lower selectivity,
and amides with a methylene moiety inserted between the
heterocycle and the amino group exhibited worse isoform
selectivity against JNK1. The rationales for isoform selectivity
of JNK3 over JNK1 have been elucidated in our previous
analogue 3 had no inhibitions to either JNK3 or JNK1. We
reasoned that the H-bond acceptor nitrogen in the thiazole
ring might have disturbed the optimal hinge-binding patterns
for the inhibitor to JNK3. We then switched to no-nitrogen-
containing thiophene moieties for a replacement. Indeed,
much better JNK3 inhibitory activities were observed. The 2,6-
disubstitution pattern analogue 4 gave a submicromolar IC50
JNK3 inhibition (0.8 μM) while still keeping a good isoform
selectivity against JNK1. Even higher JNK3 inhibition (and
isoform selectivity against JNK1) was observed for the 2,4-
disubstitution analogue 5 (IC : 0.2 μM). The best JNK3
26
publications.
In our previous studies, we demonstrated that, by
crystallography and sequence residue mutation studies, isoform
26
selectivity against JNK2 is not easy to achieve. Nevertheless,
we still observed fair to excellent isoform selectivity against
JNK2 in some of our lead compounds. For example (Table 1),
50
inhibitor was obtained when a 3,5-disubstituted thiophene ring
B
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a
Table 1. SAR Studies for the Amide Moiety
different sizes and shapes for their binding pockets, and that
might be the reason for the observed isoform selectivity of
JNK3 against JNK2 for some of our lead compounds.
In order to identify lead compounds for further
optimizations (Area-B, for example), in vitro DMPK and
cytotoxicity assays were performed to evaluate selected
compounds in Table 1. As shown in Table 2, these JNK3
Table 2. Data for P450 Inhibition, Microsomal Stability, and
MTT Cytotoxicity Assays for Selected JNK3 Inhibitors
mic. stability
1
a
CYP-450% inh.
t
(min)
/2
MTT cell viability at 10
b
cmpd 1A2/2C9/2D6/3A4 human mouse
μM
8
1
1
1
1
1
2
−2/−4/−29/−45
−1/−9/20/−18
−6/−19/−5/−34
32/7/0/−35
17/38/1/−20
6/8/−15/−34
49
54
92
32
33
66
8
35
20
15
16
13
24
15
103%
94%
89%
2
4
5
6
7
4
97%
112%
104%
95%
36/64/32/21
a
b
%
inh. at 10 μM. Data were the average of ≥2 experiments
performed in SHSY5Y cells.
inhibitors were clean in CYPs inhibitions and they exhibited
low inhibitory activities against the four select P450 isozymes.
Stabilities in human and mouse microsomes were also fair to
good for most compounds listed in Table 2. In the human
microsome, amides with a nitrogen-containing heterocyclic
ring gave better stability than those compounds with an
oxygen-containing heterocyclic ring (12/14 vs 15/16).
Interestingly, the opposite trend was observed in cytotoxicity
assays; compounds with an oxygen-containing heterocyclic
ring demonstrated lower toxicity than compounds with a
nitrogen-containing heterocyclic ring (16/17 vs 12/14).
Although compound 24 was very potent for JNK3 and had
isoform selectivity, it had serious liability in human microsomal
stability. Therefore, based on overall consideration of JNK3
inhibitory potency, isoform selectivity (against JNK1/JNK2),
in vitro DMPK properties, and cytotoxicity, compounds 16
and 17 were selected as new leads for further optimizations.
In our previous SAR studies for this pyrazole-urea scaffold,
we reported that, among monosubstituted (on the aniline
moiety) analogues, the 2-Cl substitution was the best in terms
16
of JNK3 inhibitory potency and selectivity. The crystal
structure of lead 2 in JNK3 indicated that Area-B (see Figure
1
) of compounds derived from this chemotype binds to the
selectivity pocket of JNK3, and only small substitutions (other
than the 2-Cl) to the phenyl ring could be tolerated.
16
Therefore, F-substitution will be applied to further optimize
Area-B of leads 16 and 17. This extra F-substitution is
expected to stabilize the aniline moiety, thus could lead to
improved DMPK properties. In addition, the electron-with-
drawing character of an F-substituent might also be able to
reduce the potential metabolic toxicities associated with
anilines.
As shown in Figure 3, the 6-F substituted analogue 25 gave a
similar JNK3 inhibitory potency, while the 4-F substituted
analogue 26 exhibited a slightly lower potency as compared to
lead 17. Performing α-methylation to the thiophene ring of 25
resulted in a compound (27) which also had a slightly reduced
JNK3 inhibitory potency. On the other hand, applications of
a
aIC5 is the mean of ≥2 experiments with errors within 30% of the
0
b
c
mean. Not determined. R: ratio of IC values for JNK1, JNK2 over
JNK3
5
0
compounds 14, 15, and 24 all had a JNK2 IC50 value in the
micromolar range and gave an isoform selectivity vs JNK3
between 20- and 30-fold; compounds 8, 12, and 17 exhibited
an even better selectivity of around 40-fold. An exceptionally
high isoform selectivity was observed for compound 16, which
is >250-fold. Although the residues inside and around the
binding pockets are almost identical, we believe that the
sequence difference between JNK2 and JNK3 can still yield
C
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inhibition and had further increased the general kinase
selectivity.
Crystallography studies were applied to reveal rationales for
the favored JNK3 inhibition of this thiophenyl pyrazolourea
chemotype. Thus, cocrystal structures of inhibitors 17, 25 and
2
7 (shown in the TOC Graphic) with human JNK3 were
pursued. The 1.84 Å crystal structure of 17 (Figure 4) showed
Figure 3. Further optimizations to lead inhibitors 16 and 17 (Area-B
optimizations and methylation to the thiophene ring).
both a 6-F substitution and an α-methylation (on the
thiophene ring) to 16 resulted in a compound (28) which
had a 7-fold reduction in JNK3 inhibitions. It is important to
point out that new compounds incorporating these structural
modifications still had high selectivity against p38α and still
kept a high isoform selectivity against JNK1 (all >100-folds)
and JNK2.
Figure 4. Overlay X-ray crystal structure of inhibitor 17 in human
JNK3 (2.0 Å).
As shown in Table 3, the fluorinated analogues were also
clean in CYP inhibitions, and their cytotoxicity were still low at
that, in the ATP-binding pocket, the pyrazole nitrogen atom
and the amide NH moiety H-bonded to hinge residue M149 of
JNK3. Another key H-bonding interaction from this mode was
the water-bridged H-bonds between the aniline-urea NH and
Table 3. Data for P450 Inhibition, Microsomal Stability, and
MTT Cytotoxicity Assays for Optimized JNK3 Inhibitors
the side-chain NH of residue K93. Water-bridged H-bonds
2
were also observed for the amide carbonyl group with nearby
protein residues. The amide heterocyclic ring pointed to the
outside of the binding pocket, and toward the solvent. The
aniline moiety bound to hydrophobic pocket-I (the selectivity
pocket), which is responsible mainly for the isoform selectivity
against JNK1. The thiophenyl moiety positioned around
hydrophobic pocket-II and its aromatic ring was a little
twisted (∼30°) with the central pyrazole ring. Hydrophobic
interactions in both hydrophobic pocket-I and hydrophobic
pocket-II and that around the pyrazole ring all contributed to
the high JNK3 affinity.
mic. stability
1
a
CYP-450% inh.
t
(min)
/2
MTT cell viability at 10
b
cmpd 1A2/2C9/2D6/3A4 human mouse
μM
2
2
2
2
5
6
7
8
36/48/31/24
38/47/30/−5
22/33/1/16
34/35/17/26
100
>120
110
72
68
57
38
102%
104%
111%
114%
40
a
b
%
inh. at 10 μM. Data were the average of ≥2 experiments
performed in SHSY5Y cells.
This crystal structure binding mode provides the rationales
for the high general selectivity of the thiophene-pyrazolo-urea
based JNK3 inhibitors. Basically, there are two major reasons:
(1) binding to the Selectivity Pocket which is unique to
JNK3; (2) the existence of a urea moiety in these
compounds, located right under the P-loop. In most other
ATP-competitive kinase inhibitors, the corresponding position
is normally a large aromatic ring, which renders strong
hydrophobic interactions and not much differentiation among
various kinases.
1
0 μM. As expected, the microsomal stabilities (in both human
and mouse microsomes) were much higher as compared to
leads 16 and 17. Interestingly, α-methylation to the thiophene
ring resulted in a lower microsomal stability in mice (27 vs
2
6
2
5).
Kinase panel profiling studies were applied to evaluate the
general selectivity of lead JNK3 inhibitors. Thus, 17 and 25 at
μM and 27 at 10 μM (the profiling concentration was set to
be ≥100-fold of the JNK3 IC value of each compound) were
5
We previously reported that JNK3 phosphorylates APP and
facilitates its rapid endocytosis and processing, producing
50
subjected to profiling studies against a panel of ∼374 wild-type
kinases (Reaction Biology Corporation, www.reactionbiology.
com). Data (see Supporting Information) showed that all three
compounds had significant inhibition (>80% inhibition)
against only JNK3 at the profiled concentrations. These results
demonstrated that JNK3 inhibitors derived from this
thiophenyl-pyrazolourea scaffold had not only isoform
selectivity (vs JNK1/2) but also a broadly high selectivity
against other kinases. Moreover, the profiling data revealed
that replacement of the phenyl ring in our previously published
inhibitors (leads 1 and 2) by a thiophenyl ring favored JNK3
4
Aβ42. Aβ42 then activates AMP-activated protein kinase
(AMPK) in neurons, which inhibits the mTOR translational
pathway by phosphorylating Raptor. This translational block
leads to ER stress, which activates JNK3 again, forming a
positive feedback loop that accelerates Aβ42 production. To
assess the feasibility of applying our newly developed JNK3
inhibitors to reduce and/or to slow down this process, we
evaluated the cell-based inhibition capability of selected
T668
compounds on the phosphorylation of APP . As shown in
Figure 5 (A,B,C), JNK3 inhibitors 17, 26, and 28 significantly
D
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inhibited the phosphorylation of residue T668 of APP, even at
a concentration of as low as 10 nM.
ASSOCIATED CONTENT
sı Supporting Information
■
*
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00533.
1
Details for the synthesis of 3−28; H NMR data; LC-
MS data; procedures for bioassays and DMPK studies;
kinase panel profiling data for 17, 25, and 27; cocrystal
structures of 17, 25, and 27 in human JNK3 (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Yangbo Feng − Reaction Biology Corporation, Malvern,
Pennsylvania 19355, United States; orcid.org/0000-
0002-5894-9476; Email: yangbof@gmail.com
Sung OK Yoon − Department of Biological Chemistry &
Pharmacology, Ohio State University College of Medicine,
Columbus, Ohio 43210, United States; Email: sung.yoon@
osumc.edu
Figure 5. Cell-based inhibition of APPT668 phosphorylation in primary
neurons in the presence or absence of JNK3 inhibitors: (A) 17, (B)
Authors
26, and (C) 28.
HaJeung Park − Crystallography Core Facility, Scripps
Florida, TSRI, Jupiter, Florida 33458, United States
Luke Bauer − Department of Biological Chemistry &
Pharmacology, Ohio State University College of Medicine,
Columbus, Ohio 43210, United States; orcid.org/0000-
Finally, in vivo brain exposure experiments were performed
for compound 17 in mice to assess the oral bioavailability and
brain penetration capability of lead JNK3 inhibitors. As shown
in Table 4, po dosing for compound 17 exhibited significant
brain presence of the JNK3 inhibitor, indicating that 17 is
brain penetrant and has oral bioavailability.
0003-4440-6195
Jae Cheon Ryu − Department of Biological Chemistry &
Pharmacology, Ohio State University College of Medicine,
Columbus, Ohio 43210, United States
Table 4. Brain and Plasma Concentration of Inhibitors 17 in
a
Mice
Complete contact information is available at:
https://pubs.acs.org/10.1021/acsmedchemlett.0c00533
cmpd (dosing)
plasma concentration
brain concentration
1
7 (po, 10 mg/kg)
0.96 μM
1.08 μM
Notes
a
Data were generated from more than three determinations, and
The authors declare no competing financial interest.
The coordinates of JNK3:17, JNK3:25, and JNK3:27
complexes were deposited under PDB ID 7KSK, 7KSJ and
samples collected 1 h after dosing. Formulation: DMSO/PEG400/
PBS: 1:4:5 by volume.
7KSI, respectively.
Biographies
In summary, we have developed a class of highly selective
including isoform selectivity) and potent JNK3 inhibitors
based on a thiophenyl pyrazolourea chemotype. The optimized
inhibitors had significant inhibition to only JNK3 in a panel of
Yangbo Feng is Director of Medicinal Chemistry at Reaction Biology
Corporation (RBC). His research interests are in small molecule drug
discovery focusing on CNS and oncology diseases. Yangbo received
his Ph.D degree from University of California, San Diego under the
guidance of Professor Murray Goodman. Subsequently he joined
Professor Kevin Burgess’s group at Texas A&M University, College
Station to pursue postdoctoral researches. Prior to joining RBC,
Yangbo was Associate Scientific Director of Medicinal Chemistry in
the Translational Research Institute of Scripps Florida, where he
directed a research group focusing on chemical biology, medicinal
chemistry, and combinatorial chemistry.
(
3
74 wild-type kinases, and were potent in inhibiting the
T668
phosphorylation of APP
of primary cortical and hippo-
campal neurons. Compared to the starting lead compound 2,
the replacement of the phenyl ring (as in 2) by a thiophenyl
ring had significantly improved the general selectivity against
other kinases. In addition, the newly optimized JNK3
inhibitors had good in vitro and in vivo DMPK properties,
and more importantly had oral bioavailability and were brain
penetrant, which are important for CNS applications.
Compared to other reported JNK3 inhibitors, our thiophenyl
pyrazolourea based JNK3 lead compounds have both high
selectivity (including isoform selectivity) and excellent in vivo
PK properties. Future research for these optimized JNK3
inhibitors will mainly focus on pharmacodynamics and in vivo
efficacy studies in animal models against various neuro-
degenerative diseases, such as AD and PD. These studies will
be reported in due course.
Sung Ok Yoon is a professor in the Department of Biological
Chemistry and Pharmacology at the Ohio State University Medical
School. She directs a research group that focuses on understanding
neurodegenerative diseases, such as Alzheimer’s disease. A goal of her
team is to utilize the research toward developing inhibitors to treat
these diseases.
ACKNOWLEDGMENTS
■
This work was supported by NIH/NIA grant RO1AG055059
(S.O.Y and Y.F) and ADDF (S.O.Y).
E
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(
14) de Lemos, L.; Junyent, F.; Verdaguer, E.; Folch, J.; Romero, R.;
ABBREVIATIONS
■
Pallas, M.; Ferrer, I.; Auladell, C.; Camins, A. Differences in activation
of ERK1/2 and p38 kinase in Jnk3 null mice following KA treatment.
J. Neurochem. 2010, 114, 1315−22.
JNK, c-jun N-terminal kinases; ATP, adenosine triphosphate;
AD, Alzheimer’s disease; PD, Parkinson’s disease; ALS,
Amyotrophic lateral sclerosis; SAR, structure−activity relation-
ship; DMPK, drug metabolism and pharmacokinetics.
(15) Genabai, N. K.; Ahmad, S.; Zhang, Z.; Jiang, X.; Gabaldon, C.
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