Discovery of 4-Piperazine Isoquinoline Derivatives as Potent and Brain-Permeable Tau Prion Inhibitors with CDK8 Activity

Article abstract of DOI:10.1021/acsmedchemlett.9b00480

Tau prions feature in the brains of patients suffering from Alzheimer's disease and other tauopathies. For the development of therapeutics that target the replication of tau prions, a high-content, fluorescence-based cell assay was developed. Using this high-content phenotypic screen for nascent tau prion formation, a 4-piperazine isoquinoline compound (1) was identified as a hit with an EC₅₀ value of 390 nM and 0.04 K_p,uu. Analogs were synthesized using a hypothesis-based approach to improve potency and in vivo brain penetration resulting in compound 25 (EC₅₀ = 15 nM; K_p,uu = 0.63). We investigated the mechanism of action of this series and found that a small set of active compounds were also CDK8 inhibitors.

Full text of DOI:10.1021/acsmedchemlett.9b00480

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Letter
Discovery of 4‑Piperazine Isoquinoline Derivatives as Potent and
Brain-Permeable Tau Prion Inhibitors with CDK8 Activity
Jean-Marc M. Grandjean, Alexander Y. Jiu, John W. West, Atsushi Aoyagi, Daniel G. Droege,
Manuel Elepano, Makoto Hirasawa, Masakazu Hirouchi, Ryo Murakami, Joanne Lee, Koji Sasaki,
Shimpei Hirano, Takao Ohyama, Benjamin C. Tang, Roy J. Vaz, Masahiro Inoue, Steven H. Olson,
Stanley B. Prusiner, Jay Conrad,* and Nick A. Paras
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ABSTRACT: Tau prions feature in the brains of patients suffering from Alzheimer’s disease and other tauopathies. For the
development of therapeutics that target the replication of tau prions, a high-content, fluorescence-based cell assay was developed.
Using this high-content phenotypic screen for nascent tau prion formation, a 4-piperazine isoquinoline compound (1) was identified
as a hit with an EC50 value of 390 nM and 0.04 Kp,uu. Analogs were synthesized using a hypothesis-based approach to improve
potency and in vivo brain penetration resulting in compound 25 (EC50 = 15 nM; Kp,uu = 0.63). We investigated the mechanism of
action of this series and found that a small set of active compounds were also CDK8 inhibitors.
KEYWORDS: Tau, neurodegeneration, phenotypic assay, prion, CDK8, brain permeation
0N4R(P301S)Tau-YFP. Using this cell line, we posited that hit
ggregation of the tau protein in the CNS is a pathological
Ahallmark of neurodegenerative diseases that include compounds that prevented or slowed formation of nascent
0N4R(P301S)Tau-YFP puncta in T24(S) HEK cells was used
as the starting point for a drug discovery program for
tauopathy.
Alzheimer’s disease, chronic traumatic encephalopathy, corti-
cobasal degeneration, and progressive supranuclear palsy,
among others.1 These diseases, collectively known as
tauopathies, are caused by tau prions that induce templated
misfolding of unstructured tau and its subsequent spread
throughout the brain.2,3 Thus, therapeutic agents that slow the
spread of tau prions in the brain or clear tau prion aggregates
may constitute an effective strategy for the discovery of
disease-altering treatments for tauopathy patients.
Over the past few years, our group and others have
developed cell assays to model tau propagation using cell lines
that express mutant human tau linked to YFP.4,5 When these
cells are exposed to patient-derived tau, cellular tau undergoes
templated misfolding, which induces the formation of
fluorescent puncta. We hypothesized that this concept could
provide the basis for a phenotypic high-content screen. To
match the tau isoform expressed in the Tg2541+/+ mouse
model,6 we created a HEK 293T cell line expressing human
Compound 1 was identified from a phenotypic high-content
screening campaign in T24(S) HEK cells (Figure 1). This
compound possessed good initial potency with an EC50 value
of 390 nM but low stability in mouse microsomes (2% of
parent remaining after 30 min incubation). Other ADME
parameters were encouraging; 1 showed high in vitro
permeability (PA‑B = 53.2 × 10−6 cm/s) with a low efflux
ratio (ER = 1.7)7 in LLCPK (mdr1) cells, and its calculated
physicochemical properties led to a high CNS MPO8,9 score of
Received: October 17, 2019
Accepted: January 14, 2020
https://dx.doi.org/10.1021/acsmedchemlett.9b00480
© XXXX American Chemical Society
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A

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Table 2. Amide Replacement: Effect on EC50 and MS
Figure 1. High-content screening hit in T24(S) cells.
5.75 out of 6. The latter finding suggests that 1 might be brain-
penetrant in vivo.
To determine the baseline brain permeability for com-
pounds in this series, 1 was dosed orally in B6/J mice, and
their brains were collected after 2 h. Despite its low LLCPK
(mdr1) efflux ratio and high CNS MPO score, a low unbound
brain/blood partition constant (Kp,uu = 0.04) was observed for
1 in vivo, indicating that it was a likely substrate for efflux
transporters (Table 1). Given the discrepancy between in vitro
Table 1. Polar Group Effect on Kp,uu
a
% remaining after 30 min incubation with mouse microsomes.
heterocycles. Isomeric pyrazoles 7 and 8 showed vastly
different cell activity, indicating that heterocycles are tolerated
but the position of the methyl substituent is critical.
Additionally, replacing methyl (8) with isopropyl (9) further
improved activity. Compound 9 was the first analog generated
with potency (EC50 = 170 nM) greater than compound 1,
although metabolic stability was greatly reduced (MS = 1%).
Thiazole-bearing compounds 10 and 11 were also active but
suffered from diminished metabolic stability (10, MS = 13%;
11, MS = 1%). Oxazoles 13 and 14 confirmed the trend
observed for 8 and 9, where a methyl to cyclopropyl change
affords an improvement in EC50, while expansion to a tert-butyl
decreased activity (15). However, despite the advances in
activity and metabolic stability observed for selected
compounds in Table 2, we still desired additional improve-
ments in EC50.
To improve the inhibition of tau prion activity, we adopted a
rigidification strategy for the series. The calculated low energy
conformations11 of the most potent methyl-substituted
compounds, 10 and 13, have the piperazine-amide carbonyl
in the plane with the heterocycle due to either a weak
hydrogen bond between the carbonyl oxygen and the
heterocycle12 in 13 or a noncovalent interaction between
oxygen and the thiazole sulfur13 in 10 (Table 2). If the
conformations favoring these putative intramolecular inter-
actions were responsible for the enhanced activity of these
compounds, replacing the amide with a [6,5]-fused heterocycle
should lead to improvements in activity (Table 3). This
strategy was particularly successful in the case of indazole 18,
which had an EC50 of 22 nM and maintained acceptable
microsomal stability (MS = 46%). Interestingly, regioisomer
21 was more than five times less active than 18 while
benzoxazoles 16 and 17 were inactive despite the comparable
activities of oxazoles and pyrazoles in Table 2. Pyrido-
imidazole 22 and pyrido-pyrrole 23 were less active than the
indazoles, and both analogs of 18, compounds 19 and 20,
bearing either a 7-N or 7-C-F were inactive in the assay,
indicating that stereoelectronic factors may influence activity.
a
compound EC50 (μM) Cplasma (μM) Cbrain (μM)
Kp
Kp,uu
b
b
1
2
3
0.39
0.91
>10.0
2.8
1.0
1.5
0.2
0.4
1.2
0.07
0.4
0.8
0.04
0.2
0.4
c
c
c
c
a
b
B6/J mice, 10 mg/kg (gavage, 0.5% MC). Plasma and brain
concentrations at 0.5 h post administration. Plasma and brain
c
concentrations at 1 h post administration.
ER and in vivo Kp observed for 1, further optimization was
guided by in vivo Kp. To better understand how polar moieties
interact with transporters to recognize 1, we synthesized
compounds 2 and 3, wherein either the thiophene amide or
the isoquinoline nitrogen were removed. Improved in vivo
unbound partition coefficients were observed for the
compounds (2, Kp,uu = 0.2; 3, Kp,uu = 0.4), suggesting that
the high hydrogen-bond avidity of both moieties10 could
contribute to transporter recognition. With two potential
avenues to reduce efflux, we decided to focus on thiophene
amide replacement rather than isoquinoline modification.
Compared with compound 1, 2 greatly improved Kp,uu
combined with reduced molecular weight (2, 297 g/mol; 1,
394 g/mol), while only sacrificing about 2-fold in cell potency
(1, EC50 = 0.39 μM; 2, EC50 = 0.90 μM).
Our initial strategy for improving the activity of 2 began by
replacing the tert-butyl with a heteroatom containing
substituents on the piperazine amide (Table 2). We were
encouraged by tetrahydrofuran 4 and oxetane 5, which
retained activity while maintaining acceptable metabolic
stability. Substituted pyrazoles, oxazoles, and thiazoles were
synthesized to survey activity and metabolic stability of
B
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The increased Kp,uu achieved with 3 suggested that reducing
the isoquinoline pKa would lead to improved brain exposure.
As summarized in Table 5, we observed that the introduction
Table 3. Rigidification Strategy to Improve Activity
Table 5. Strategy to Increase Activity and Kp,uu
a
% remaining after 30 min incubation with mouse microsomes.
a
b
% remaining after 30 min incubation with mouse microsomes. B6/J
mice, plasma, and brain concentrations at 2 h post administration, 10
mg/kg (gavage, 0.5% MC).
Compound 18 was tested in a mouse PK experiment to
determine its Kp at 2 h post administration (Table 4). Despite
Table 4. Effect of [6,5]-Fused Rings on Kp,uu
of electron-withdrawing substituents at the isoquinoline 6-
position was well-tolerated in the assay. In particular, 25 and
26 with hydrogen-bond acceptors were very active tau
aggregation inhibitors (EC50 (25) = 15 nM; EC50 (26) = 35
nM). Furthermore 25, 26, and 27 achieved high unbound
brain/blood partition coefficients. It is possible that any
negative contribution toward efflux caused by these polar
substituents was offset by the concomitant reduction of
isoquinoline pKa. In any event, compounds 25 and 26 became
our new benchmarks with high potency and good brain
exposure.
a
a
T24(S) EC50 (μM) Cplasma (μM) Cbrain (μM)
Kp
Kp,uu
As a first step toward elucidating the mechanism of action of
compounds in this series, we engaged in a literature similarity
search. In particular, our search focused on biologically active
substituted quinolines bearing cyclic moieties at the 4-position.
We quickly identified BI-134714,15 (labeled 28), a potent
CDK8/cyclinC16 inhibitor discovered by Boehringer Ingel-
heim, with a reported in vitro IC50 of 1 nM. We were struck by
the resemblance between 28 and the 4-piperazine-substituted
isoquinolines described in Figure 2. We tested BI-1347 in the
T24(S) cell assay and found it to be a potent tau aggregation
inhibitor with an EC50 of 5 nM. To assess whether CDK8 was
a potential target for compounds in our series, we selected
three analogs with differing cell EC50s for CDK8 Kd
determination. Comparing intrinsic EC50 in the tau aggrega-
tion assay (cell assay activities corrected for free fraction in
medium) and CDK8 Kd, we found that more active tau
aggregation inhibitors had lower CDK8 Kd (Table 6).
Published data for BI-134714 indicated that it is selective for
CDK8 and its paralog CDK19 over other kinases, and a screen
for 25 (included in the SI1) showed that it is selective for
CDK8/19 over 468 kinases tested except for PI4KB.
18
20
21
0.022
>10
0.12
11.4
3.2
9.0
0.15
3.9
6.80
0.01
1.2
0.75
0.005
0.53
0.35
a
B6/J mice, plasma, and brain concentrations at 2 h post
administration, 10 mg/kg (gavage, 0.5% MC).
its low PSA (37.2 Å2) and deletion of the tertiary amide, 18
showed poor brain exposure in mice (Kp = 0.01; Kp,uu = 0.05),
much lower than that observed for 2. Although less active than
18, compounds 20 and 21 were tested in vivo to determine the
factors governing efflux for indazole derivatives. Compound 20
was chosen to assess whether fluorination and subsequent
lowering of indazole pKa could improve brain penetration.
Conversely, 21 was identified as an active analog where the
directionality of the basic nitrogen and the methyl substituent
were modified relative to 18, in an attempt to disrupt
recognition by efflux transporters. Both 20 and 21 had
significantly improved unbound brain/blood ratios (20, Kp,uu
=
0.53; 21, Kp,uu = 0.35), indicating the importance of the
indazole stereoelectronics in transporter recognition. Given
that 21 was still active in the tau prion bioassay (EC50 = 120
nM), we focused on improving the potency of this compound.
Compounds 28, 25, 21, and 13 (along with 29,17 a CDK8
inhibitor (IC50 of 0.9 nM; EC50 of 9 nM in the T24(S) assay)
C
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cannot engage in this π−π interaction, providing a reasonable
explanation for its higher Kd (600 nM).
Given the activity of BI-1347 as an inhibitor of tau
aggregation, it was tested in in vivo Kp and found to distribute
poorly to the brain (Kp,uu = 0.01) (Table 6). On the other
hand, 21 and 25 are potent CDK8 inhibitors capable of
crossing the BBB (Kp,uu(21) = 0.35 and Kp,uu(25) = 0.63). To
the best of our knowledge, these are the first examples of
CDK8 inhibitors with in vivo BBB permeability and low efflux.
The correlation between CDK8 inhibition and tau aggregation
inhibition is under further investigation. However, the
discovery of brain-penetrant CDK8 inhibitors could be of
interest to the oncology community.
In summary, we optimized a series of 4-piperazine
isoquinoline compounds that inhibit tau prion activity. SAR
studies were guided by optimization of compound activity and
improvements to in vivo brain exposure in mice. Improvements
to Kp,uu were achieved through rational design and key
experiments to identify the structural elements responsible for
high BBB efflux. A similarity search identified the CDK8
inhibitor BI-1347 as a potent tau prion inhibitor in our T24(S)
cell assay. Compounds from the 4-piperazine isoquinoline
series were found to be potent, brain-penetrant CDK8
inhibitors, and their binding to CDK8 was further supported
by docking studies. Efforts toward the optimization of these tau
prion inhibitors are ongoing.
Figure 2. Docking to CDK8 crystal structure. (A) 28 and 29, (B) 25,
(C) 21, and (D) 13 docked to 5ICP.
Table 6. CDK8 Inhibition Relative to BI-1347
ASSOCIATED CONTENT
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sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00480.
a
b
EC50 (μM)
intEC50 (nM)
CDK8 Kd (nM)
Kp,uu
Experimental procedures for compound synthesis and
characterization, biological assays, computation meth-
ods, and kinase selectivity data for compound 25 (PDF)
13
21
25
28
0.22
0.12
0.015
0.005
210
30.0
5.0
600
30.0
32.0
0.07
0.35
0.63
0.01
2.0
0.77
a
b
AUTHOR INFORMATION
EC50 corrected for protein binding in assay medium. Determined
■
from in vivo Kp at 2 h, 10 mg/kg (gavage, 0.5% MC).
Corresponding Author
Jay Conrad − Institute for Neurodegenerative Diseases (IND),
UCSF Weill Institute for Neurosciences, University of California,
San Francisco, San Francisco, California 94518, United States;
orcid.org/0000-0002-9048-8833; Email: jay.conrad@
ucsf.edu
of similar structure) were docked to a known cocrystal
structure of CDK818 and 29 (Figure 2). In accordance with the
reported structure,19 key interactions for binding of 29 were
reproduced in silico, namely amide binding to Lys52, hinge
binding to Ala100, and a cation−π interaction with Arg356.
The docked structures of 28 and 29 (Figure 2A) adopt a
similar orientation, although 28 extends further and has an
additional π−π interaction between its pyrazole ring and
His106. Combined, these interactions account for the very low
Kd (0.77 nM) observed for this ligand. Compounds 25, 21, and
13 were predicted to bind in the same orientation as 28 with
the isoquinoline nitrogen interacting with Ala100. Analogous
to 29 the methyl ketone of 25 made a hydrogen bond to
Lys52. We postulate that the lower activity of 25, 21, and 13
compared to the previously published compounds is due to the
replacement of phenyl with piperazine and subsequent loss of
the cation−π interaction with Arg356. Interestingly, in the case
of 25 and 21 the face of the indazole ring makes a close
interaction with the edge of His106. These interactions are
likely to be strong given the proximity of His106 to Asp103
and Arg356 and the fact that His106 may be partially charged.
The oxazole in compound 13 points away from His106 and
Authors
Jean-Marc M. Grandjean − Institute for Neurodegenerative
Diseases (IND), UCSF Weill Institute for Neurosciences,
University of California, San Francisco, San Francisco,
California 94518, United States
Alexander Y. Jiu − Institute for Neurodegenerative Diseases
(IND), UCSF Weill Institute for Neurosciences, University of
California, San Francisco, San Francisco, California 94518,
United States
John W. West − Institute for Neurodegenerative Diseases (IND),
UCSF Weill Institute for Neurosciences, University of California,
San Francisco, San Francisco, California 94518, United States
Atsushi Aoyagi − R&D Division, Daiichi Sankyo Co., Ltd.,
Tokyo 140-8710, Japan
Daniel G. Droege − Institute for Neurodegenerative Diseases
(IND), UCSF Weill Institute for Neurosciences, University of
California, San Francisco, San Francisco, California 94518,
United States
D
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Letter
Manuel Elepano − Institute for Neurodegenerative Diseases
(IND), UCSF Weill Institute for Neurosciences, University of
California, San Francisco, San Francisco, California 94518,
United States
Makoto Hirasawa − R&D Division, Daiichi Sankyo Co., Ltd.,
Tokyo 140-8710, Japan
Masakazu Hirouchi − R&D Division, Daiichi Sankyo Co., Ltd.,
Tokyo 140-8710, Japan
Ryo Murakami − R&D Division, Daiichi Sankyo Co., Ltd.,
Tokyo 140-8710, Japan
Joanne Lee − Institute for Neurodegenerative Diseases (IND),
UCSF Weill Institute for Neurosciences, University of California,
San Francisco, San Francisco, California 94518, United States
Koji Sasaki − R&D Division, Daiichi Sankyo Co., Ltd., Tokyo
140-8710, Japan
Shimpei Hirano − R&D Division, Daiichi Sankyo Co., Ltd.,
Tokyo 140-8710, Japan
Takao Ohyama − R&D Division, Daiichi Sankyo Co., Ltd.,
Tokyo 140-8710, Japan
Benjamin C. Tang − Institute for Neurodegenerative Diseases
(IND), UCSF Weill Institute for Neurosciences, University of
California, San Francisco, San Francisco, California 94518,
United States
Roy J. Vaz − Institute for Neurodegenerative Diseases (IND),
UCSF Weill Institute for Neurosciences, University of California,
San Francisco, San Francisco, California 94518, United States
Masahiro Inoue − R&D Division, Daiichi Sankyo Co., Ltd.,
Tokyo 140-8710, Japan
Steven H. Olson − Institute for Neurodegenerative Diseases
(IND), UCSF Weill Institute for Neurosciences, University of
California, San Francisco, San Francisco, California 94518,
United States
pharmacokinetics; PSA, polar surface area; SAR, structure
activity relationship; YFP, yellow fluorescent protein
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Funding
This work was supported by a grant from the National
Institutes of Health (AG002132) (S.B.P.), as well as by
support from the Brockman Foundation (S.B.P.) and the
Sherman Fairchild Foundation (S.B.P.).
Notes
The authors declare the following competing financial
interest(s): The Institute for Neurodegenerative Diseases has
a research collaboration with Daiichi Sankyo (Tokyo, Japan).
Stanley B. Prusiner is a member of the Scientific Advisory
Board of ViewPoint Therapeutics and a member of the Board
of Directors of Trizell, Ltd., neither of which have contributed
financial or any other support to these studies.
ABBREVIATIONS
■
(17) Mallinger, A.; Schiemann, K.; Rink, C.; Sejberg, J.; Honey, M.
A.; Czodrowski, P.; Stubbs, M.; Poeschke, O.; Michael, B.; Schneider,
R.; Schwarz, D.; Musil, D.; Burke, R.; Urbahns, K.; Wienke, D.;
Clarke, P. A.; Raynaud, F. I.; Eccles, S. A.; Rohdich, F.; Blagg, J. 2.8-
BBB, blood brain barrier; ER, efflux ratio; CNS MPO, central
nervous system multiparameter optimization; HEK, human
embryonic kidney; LLCPK, pig kidney cell line; PK,
E
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2016, 7, 573.
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O.; Busch, M.; Rohdich, F.; Eccles, S. A.; Ortiz-Ruiz, M.-J.; Schneider,
R.; Raynaud, F. I.; Clarke, P. A.; Musil, D.; Schwarz, D.; Dale, T.;
Urbahns, K.; Blagg, J.; Schiemann, K. Structure-Based Optimization of
Potent, Selective, and Orally Bioavailable CDK8 Inhibitors Discov-
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(19) PDB code: 5I5Z.
F
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