Discovery of CPI-1612: A Potent, Selective, and Orally Bioavailable EP300/CBP Histone Acetyltransferase Inhibitor

Article abstract of DOI:10.1021/acsmedchemlett.0c00155

The histone acetyltransferases, CREB binding protein (CBP) and EP300, are master transcriptional co-regulators that have been implicated in numerous diseases, such as cancer, inflammatory disorders, and neurodegeneration. A novel, highly potent, orally bioavailable EP300/CBP histone acetyltransferase (HAT) inhibitor, CPI-1612 or 17, was developed from the lead compound 3. Replacement of the indole scaffold of 3 with the aminopyridine scaffold of 17 led to improvements in potency, solubility, and bioavailability. These characteristics resulted in a 20-fold lower efficacious dose for 17 relative to lead 3 in a JEKO-1 tumor mouse xenograft study.

Full text of DOI:10.1021/acsmedchemlett.0c00155

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Letter
Discovery of CPI-1612: A Potent, Selective, and Orally
Bioavailable EP300/CBP Histone Acetyltransferase (HAT) Inhibitor
Jonathan E Wilson, Gaurav Patel, Chirag Patel, Francois Brucelle, Annissa Huhn, Anna S Gardberg, Florence
Poy, Nico Cantone, Archana Bommi-Reddy, Robert J. Sims, Richard T. Cummings, and Julian R. Levell
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.0c00155 • Publication Date (Web): 23 Apr 2020
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Discovery of CPI-1612: A Potent, Selective, and Orally Bioavailable
EP300/CBP Histone Acetyltransferase (HAT) Inhibitor
Jonathan E. Wilson*, Gaurav Patela, Chirag Patela, Francois Brucelleb, Annissa Huhnc, Anna S.
Gardberg, Florence Poy, Nico Cantone, Archana Bommi-Reddy, Robert J. Sims IIId, Richard T.
Cummings, Julian R. Levell
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Constellation Pharmaceuticals, 215 First Street, Suite 200, Cambridge, MA 02142, United States
KEYWORDS: p300, CBP, histone acetyltransferase, HAT, KAT
ABSTRACT: The histone acetyltransferases, CBP and EP300, are master transcriptional co-regulators that have been implicated in
numerous diseases, such as cancer, inflammatory disorders, and neurodegeneration. A novel, highly potent, orally bioavailable
EP300/CBP HAT inhibitor, CPI-1612 or 17, was developed from the lead compound 3. Replacement of the indole scaffold of 3
with the aminopyridine scaffold of 17, led to improvements in potency, solubility, and bioavailability. These characteristics resulted
in a 20-fold lower efficacious dose for 17 relative to lead 3 in a JEKO-1 tumor mouse xenograft study.
N
N
Me
N
O
Me
O
H
H
N
N
N
Me
N
N
H
HN
Lead Optimization
CN
CN
3
17
EP300 HAT SPA IC50 = 40 nM
mouse F% = 24
EP300 HAT SPA IC50 = 8.0 nM
mouse F% = 79
in vivo efficacy @ 10 mg/kg PO BID
hERG inhibition (10 M) = 99%
in vivo efficacy @ 0.5 mg/kg PO BID
hERG inhibition (10 M) = 9%
EP300 and CBP, also known as KAT3A/3B, are two highly
homologous, multidomain, epigenetic regulatory enzymes
that affect transcription. Although their transcriptional
effects are mediated through multiple mechanisms utilizing
the different functional domains of these enzymes, the
acetylation of histone lysine residues with the cofactor
acetyl coenzyme A (AcCoA) by their HAT domains plays a
central role in regulating transcription. The HAT domains
of EP300 and CBP also modulate the activity of non-
histone protein through post-translational acetylation.1 Both
enzymes have been implicated in a wide variety of human
diseases, such as cancer, inflammation, fibrosis, and
neurodegeneration, .2-7 While loss-of-function in EP300
and/ or CBP has been shown to be deleterious, double
knockout is lethal in mammals, it has also been shown that
overexpression or activating mutations can lead to disease
states, particularly in cancer.8, 9 As such, small molecule
inhibitors of EP300/CBP HAT activity may provide a
novel opportunity for therapeutic intervention in a wide
range of human diseases.10
explored the SAR of the indole, central benzene, and
phenethylamine side chain. To do this, each hydrogen atom
of compound 2, the minimum pharmacophore of lead
compound 1, was replaced with a chlorine atom or methyl
group to establish which vectors may allow for introduction
of moieties to optimize the potency and physicochemical
properties of the scaffold.12 These efforts culminated in the
identification of 3, a tool compound suitable to validate our
biochemical assays, interrogate CBP/EP300 HAT biology
in vitro, and perform initial in vivo experiments. While
compound 3 and its analogues were suitable for early proof
of concept studies, we sought to improve the potency, oral
bioavailability, solubility, and off-target profile of the
series with the goal of advancing an EP300/CBP HAT
inhibitor into clinical studies. Herein, we describe our
medicinal chemistry lead optimization efforts.
We previously described our early drug-discovery efforts
towards the identification of leads for the development of
novel EP300/CBP HAT inhibitors.11 With an emphasis on
improving the potency of the HTS hit 1, we independently
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confer improved solubility to this class of inhibitors. This
SO2NH2
CN
O
O
HN
HN
1
2
3
4
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8
led us to discover the 2-aminopyridine derivative 12, which
possessed improved potency and solubility relative to 3.
Other aminoheterocyclic scaffolds including the
regioisomeric pyridine 13, pyridazine 14, pyrazine 15, and
pyrimidine 16 were inferior to the 2-aminopyridine 12.
N
N
N
N
H
H
Me
3
1
EP300 HAT IC50 = 0.040 M
solubility < 1.0 M
hERG (% inh.@10 M) = 99%
mouse F% = 24
HTS hit
EP300 HAT IC50 = 2.5 M
In addition to its improved potency and solubility, 12 has
improved stability to epimerization, permeability and
mouse PK relative to 3. These findings led us to focus our
efforts on the optimization of the aminopyridine scaffold.
Based on earlier studies examining the effect of
9
SAR
Vector 2
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HN
O
N
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substitution of the phenethylamine side chain, a methyl
group was incorporated into the phenethylamine side chain
of 12 to provide compound 17 with the expectation that it
would improve the potency and lower the in vitro
N
SAR
Vector 1
N
H
2
minimum pharmacophore
EP300 HAT IC50 = 4.3 M
= positions substituted with methyl group
= positions substituted with chloro group
clearance.15 Indeed, this modification provided a compound
with a 2- to 3-fold improvement in potency across a range
of biochemical (EP300 HAT, full length EP300, and full
length CBP) and cell-based assays (H3K18Ac MSD and
JEKO-1 proliferation) while at the same time improving
the microsomal stability. The stereoisomers of 17 were
>40-times less potent than 17.16 Further modifications to 17
were made, including heterocyclic analogues of the
pyrazole, methyl-substituted pyridine analogues, and 2- and
3-fluoro-4-cyanophenethylamine analogues.17 While some
of these analogues provided modest improvements over 17
for a single parameter none of them were better than 17 in
aggregate and we focused our attention on 17 for further in
vivo studies.
Figure 1. Development of lead compound 3 from HTS hit 1.
The thorough investigation of the SAR outlined in Figure 1
gave us confidence that we had identified the substitution
pattern for optimal potency on the phenethylamine side
chain, central benzene, and indole core. Subsequently, we
focused our attention on the identification of replacements
for the indole system, a portion of the molecule that we had
not modified up to this stage of the program, that would
retain the potency of 3 while improving upon its
suboptimal solubility, bioavailability, and hERG inhibition.
Our initial efforts in this vein were centered on adding an
additional nitrogen atom to the indole core, either in the
form of aza-indole 4, indazole 5 or by substitution with an
indole isostere, such as imidazopyridines 6 and 7 or
pyrazolylpyridine 8. Only the pyrazolyl pyridine retained
the potency of 3 but with decreased stability in mouse liver
microsomes (Table 1). Furthermore, we noted that the
potency of compounds 3-8 converged with their respective
enantiomers in JEKO-1 cell viability experiments (data not
shown). We hypothesized that this convergence in potency
was due to compound racemization during the viability
assay which was of substantially longer duration relative to
the SPA assays.13 We also sought to address this later issue
with future analogues.
The X-ray cocrystal structure of 1 with EP300 led us to
hypothesize that the indole of 3 served mainly as a
scaffolding element to appropriately position the
phenethylamine side chain and the C-6 pyrazole group.11
This reasoning led us to speculate that a bicyclic scaffold
was not required and that it could be replaced with
scaffolds that would adopt a conformation in which the
benzenoid portion of the indole of 3 was coplanar with its
carbonyl group.14 Based on this reasoning, we chose to
explore anilines and amino-heterocyclic amines as
replacements for the indole scaffold. While indoline 9
proved to be a potent inhibitor, the compound had poor
microsomal stability. The tetrahydroquinoline 10 was not
tolerated as a replacement, likely because the
tetrahydroquinoline disrupts the coplanar relationship of
the scaffold and carbonyl group. While the aniline amide
11 was approximately 3-fold less potent than 3, it
encouraged us to explore additional amino-heterocyclic
amides with the hope of identifying a scaffold that would
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Table 1. Alternative scaffolds to the indole in compound 3.
Table 2. Structure of compound 17 and profiles of indole
lead 3, and aminopyridine analogues 12 and 17.
N
N
O
H
N
Me
N
N
Me
Scaffold
O
Me
H
CN
N
N
N
H
Ph
CN
17
EP300 HAT H3K18Ac
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kinetic mouse LM
solubility clearance
(M) (mL/min/kg)
Compound
in vitro assaysa
3
12
17
compound
scaffold
SPA
MSD
IC50 (M)a EC50 (M)a
EP300 HAT SPA IC50 (μM)
0.040
0.0025
0.0032
0.037
0.044
97
0.019
<0.0005
0.0067
0.025
0.017
n.a.
0.0081
<0.0005
0.0029
0.014
<0.0079
9.2
Full length EP300 SPA IC50 (μM)
Full length CBP SPA IC50 (μM)
H3K18Ac MSD EC50 (μM)
JEKO-1 GI50 (μM)
hERG (% inh. @ 10 μM)
PAMPA pe (nm/s)
Mouse PPB (%)
0.028
+/- 0.015
0.040
+/- 0.002
3
<1.0
NA
47
NA
361
N
H
0.036
+/- 0.004
4
NA
NA
N
N
H
<0.066
99.1
13.8
11.9
98.3
99.1
0.57
+/- 0.09
5b
NA
MLM Cl (μL/min/mg)
Mouse PKb
46.6
215
178
N
N
H
Clearance (L/h/kg)
Vss obs
3.49
1.92
1.44
43
2.30
0.88
1.24
88
1.88
0.99
1.40
47
0.097
+/- 0.009
N
N
6
7
NA
NA
NA
NA
NA
NA
T1/2 (hours)
F%
0.52
+/- 0.02
N
aAll biochemical assays are the average of two or more runs. PAMPA,
mouse PPB, and MLM assays are a single run. bMouse PK data are
derived from cassette PK experiments, using 0.5 mg/kg IV and 2.5 mg/kg
PO doses.
N
Me
0.017
+/- 0.003
8
9
NA
NA
<1.0
2.81
NA
347
355
NA
N
The high EP300 potency, promising in vitro profile, and
good mouse PK of 17 prompted us to further profile this
compound’s pharmacokinetic profile in rats and dogs.
While the oral exposure of 17 in dogs (0.5 mg/kg IV; 1.0
N
0.021
+/- 0.004
N
N
mg/kg PO; clearance = 0.42 L/h/kg, Vss = 3.7 L/kg, T1/2
=
10
>5.0
NA
NA
5.5 h, F% = 71; AUC/dose = 1,691 h*mg/mL) and mice
(1mg/kg IV; 5 mg/kg PO; clearance = 3.8 L/h/kg, Vss = 2.0
L/kg, T1/2 = 0.98 h, F% = 79; AUC/dose = 211 h*mg/mL)
is good, the exposure in rats is limited by poor
0.12
+/- 0.008
N
11
12
13
14
<1.0
23.7
NA
74
215
NA
H
bioavailability (1.0 mg/kg IV; 5.0 mg/kg PO; clearance =
2.6 L/h/kg, Vss = 1.8 L/kg, T1/2 = 1.2 h, F% = 9; AUC/dose
= 35.6 h*mg/mL).18 Additionally, because there are many
potential indications where a brain-penetrant EP300/CBP
HAT inhibitor would of interest, we performed a mouse PK
experiment to monitor for brain exposure.6, 7 In this
experiment, a single dose of 17 was administered orally to
CD-1 mice and brain and plasma exposures of 17 were
measured at 0.25, 0.5, 1.0, 2.0, 4.0, and 8.0 hours. 17 is
highly brain-penetrant showing a brain-to-plasma ratio of
0.35 after a single oral dose.19
0.019
0.025
N
+/- 0.003
+/- 0.008
N
H
2.7
+/- 0.2
N
NA
NA
N
N
H
0.46
+/- 0.02
2.96
140
N
N
N
N
H
0.77
+/- 0.02
15
16
NA
NA
NA
NA
NA
NA
N
N
H
Compound 17 was then characterized for its selectivity
against other histone acetyltransferases and a panel of
typical anti-targets. No inhibitory activity was observed in
a panel of 7 HAT targets (Tip60, HAT1, PCAF, MYST2,
MYST3, MYST4, and GCN5L2) and had minimal activity
against the anti-targets in the Eurofins Safety44 off-target
screening panel. Additionally, 17 showed weak activity in a
hERG binding assay (IC50 = 10.4 μM) and displayed
>5.00
N
N
H
aData is the average of three or more duplicate runs. Error is reported
as standard deviation. bCompound is racemic.
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moderate inhibition of CYP2C8 (IC50 = 1.9 μM) and
CYP2C19 (IC50 = 2.7 μM) but showed less inhibition of
CYP3A4, CYP2D6, CYP1A2, CYP2B6, and CYP2C9
(>50 μM, 34 μM, >50 μM, 8.2 μM, 6.6 μM).
Page 4 of 7
bonds with the backbone N-H of TYR1446 and to
ASP1399 through the aminopyridine scaffold, while A-485
makes no direct contact with this residue. Another
difference in the binding modes are the interactions of the
aromatic side chains. The 4-cyanophenethylamine side
chain of 17 interacts with TRP1466 through a π-stacking
interaction while the 4-fluorobenzylamide of A-485 fills a
pocket formed by TYR1414 and LEU1418. This later
pocket is filled by the methyl group on the phenethylamine
side chain of 17.
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X-ray cocrystal structures, obtained utilizing the
methodology described by Abbvie, clearly show that
compounds 12 and 17 bind to the acetylcoenzyme A
binding site.11 Figure 2 shows an overlay of AcCoA and 12
that highlights the major ligand-protein contacts of 12 to
the EP300 HAT domain. Several of the binding interactions
are common for indole 1 and aminopyridine 12. These
include the SER1400 H-bonding interaction to the
phenethylamine N-H and the π-stacking interactions of
TRP1466 to the phenethylamine aromatics and of HIS1451
to the indole of 1 or the aminopyridine of 12. A key
difference between the crystal structures of 1 and 12 that
may account for the improved potency of 12 relative to 3,
is a H-bonding network that is established between the
aminopyridine of 12 with ASP 1399 and a water bound to
the backone N-H of TYR1446. This water is not found in
the co-crystal structure of 1 presumably because it has been
displaced by the indole N-H.
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Figure 3. Overlay of X-ray cocrystal structures of 17 (cyan) and
A-485 (pink) bound to the HAT domain of EP300 with key
hydrogen bonds (red) and pi-stacking interactions (yellow) of A-
485 highlighted.
The in vivo activity of 17 was assessed by conducting a
PK/PD study in C57B6 mice, measuring H3K27Ac
reduction in PBMCs and H3K18Ac reduction in spleen
tissue (data not shown) after oral administration of 17. As
expected, based on its high potency and good
pharmacokinetic profile, 17 reduces the histone acetylation
in vivo at the primary chromatin acetylation targets of
EP300/CBP in a dose- and time-dependent manner (Figure
4).
Figure 2. Overlay of X-ray cocrystal structures of 12 (cyan) and
acetylcoenzyme A (pink) bound to the HAT domain of EP300
with key hydrogen bonds (red) and pi-stacking interactions
(yellow) of 12 with EP300 highlighted.
While both our series of inhibitors and Abbvie’s occupy the
AcCoA pocket of EP300, the contacts the two classes make
with the protein are somewhat distinct. While both
compounds make hydrogen bonds with SER1400, 17 does
so through an N-H bond and A-485 through a carbonyl
group from the oxazolidinedione.20, 21 The only other
interaction common to both inhibitors is a π-stacking
interaction with HIS1451. The other interactions the
compounds make with the protein are distinct. A-485
makes two hydrogen bonds from a urea moiety with the
backbone carbonyl of GLN1455, while 17 makes no direct
contact with this residue. In contrast 17 makes hydrogen
Figure 4. Dose- and time-dependent reduction of
H3K27Ac in PBMCs of C57Black6 mice after oral
administration of compound 17.
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The efficacy of 17 was then assessed in a mouse tumor
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The PDB deposition validation reports are also available as a
PDF.
xenograft model using a B-cell lymphoma line, JEKO-1,
which we have shown is sensitive to CBP/EP300 HAT
inhibition. 17 showed 67% TGI at a dose of 0.5 mg/kg PO
BID with concomitant reduction of H3K27Ac in plasma
and reduction of H3K18Ac in the tumor. These effects are
approximately equivalent to those observed with 3 when
dosed at 10 mg/kg BID PO (65% TGI). This represents a
20-fold improvement of in vivo activity for 17 relative to 3,
with an improved off-target profile. This improvement in in
vivo activity can mainly attributed to the improved potency,
permeability, and solubility of 17 relative to 3 (Figure 5).
AUTHOR INFORMATION
Corresponding Author
* Email: jonathan.wilson@constellationpharma.com
Present Addresses
a Piramal Enterprises Limited-Discovery Solutions
Ahmedabad, Gujarat, IN 382 213.
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b Foghorn Therapeutics, 100 Binney Street, Suite 610, Cambridge,
MA, USA 02142.
c Kymera Therapuetics, 300 Technology Square, Cambridge, MA,
USA 02142.
d Third Rock Ventures, 29 Newbury St #301, Boston, MA, USA
02116.
Author Contributions
The manuscript was written through contributions of all authors. /
All authors have given approval to the final version of the
manuscript.
ABBREVIATIONS
CBP, CREB binding protein; HAT, histone acetyltransferase;
AcCoA, acetyl coenzyme A; H3K27, histone 3 lysine 27; H3K18,
histone 3 lysine 18; HTS, high throughput screen; SAR, structure
activity relationship; SPA, scintillation proximity assay; MSD,
meso scale discovery; PAMPA, parallel artificial membrane
permeation assay; PPB, plasma protein binding; MLM, mouse
liver microsomes; PK, pharmacokinetics; hERG, human ether-à-
go-go-related gene or Kv 11.1; IV, intravenoues; PO, per os; TGI,
tumor growth inhibition.
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Figure 5. Antitumor activity (top), H3K18Ac reduction in
tumor (bottom left), and H3K27Ac reduction in plasma
(bottom right) of 17 (orange) and 3 (blue) in a JEKO-1
xenograft model.
In summary, we have detailed the optimization of lead
indole compound 3 into the highly potent and selective
aminopyridine EP300/CBP HAT inhibitor CPI-1612, 17. A
wide variety of scaffold replacements for the indole were
surveyed, resulting in the discovery of the aminopyridine
core of 12. Further optimization led us to compound CPI-
1612 which is potent across a range of biochemical and
cellular assays that assess EP300/CBP HAT inhibition, has
good pharmacokinetic profiles in mice and dogs, and is
devoid of any significant off-target activity. Additionally,
CPI-1612 suppresses H3K27 acetylation in vivo and is
efficacious in a JEKO-1 mantle cell lymphoma xenograft at
a low dose.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
(9) Yao, T. P.; Oh, S. P.; Fuchs, M.; Zhou, N. D.; Ch’ng, L. E.;
Newsome, D.; Bronson, R. T.; Li, E.; Livingston, D. M.; Eckner, R.
Gene Dosage–Dependent Embryonic Development and Proliferation
Defects in Mice Lacking the Transcriptional Integrator p300. Cell
1998, 93, 361-372.
The preparation of compounds 3-17, experimental details for in
vivo experiments and ADME experiments, and details for x-ray
crystallography of compounds 12 and 17 are available as a PDF.
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(10) Lasko, L.M.;Jakob, C.S.; Edalji, R.P.; Qiu, W.;Montgomery,
D.; Digiammarino, E. L.; Hansen, T. M.; Risi, R. M.; Frey, R.;
Manaves, V.; Shaw, B.; Algire, M.; Hessler, P.; Lam, L. T.; Uziel, T.;
Faivre, E.; Ferguson, D.; Buchanan, F. G.; Martin, R. L.; Torrent, M.;
Chiang, G. G.; Karukurichi, K.; Langston, J. W.; Weinert, B. T.;
Choudhary, C.; DeVries, P.; VanDrie, J.H. ;McElligott,D.;Kesicki, E.;
Marmorstein, R.; Sun, C.; Cole, P. A.; Rosenberg, S.; Michaelides, M.
R.; Lai, A.; Bromberg, K. D. Discovery of a selective catalytic
p300/CBP inhibitor that targets lineage-specific tumors. Nature 2017,
550, 128−132.
(11) Wilson, J. E.; Huhn, A.; Gardberg, A. S.; Poy, F.; Brucelle, F.;
Vivat, V.; Patel, G.; Patel, C.; Cummings, R; Sims, R.; Levell, J.;
Audia, J. E.; Bommi-Reddy, A.; Cantone, N. Early Drug Discovery
Efforts Towards the Identification of EP300/CBP Histone
Acetyltransferase (HAT) Inhibitors. ChemMedChem 2020,
doi.org/10.1002/cmdc.202000007.
(12) Data for chlorine- and nitrogen-‘walk’ studies can be found in
the associated supporting information document for reference 11.
(13) The EP300 HAT SPA enzymatic assay was run for 1 hour
while the JEKO-1 cell viability assay was run for 72 hours.
(14) The x-ray cocrystal structure of 1 clearly shows that the indole
scaffold and the 3-carbonyl group are coplanar. The x-ray structure of
1 with an EP300 HAT construct has been deposited in the PDB
(6v8b). See reference 11.
(15) In all cases we have examined, addition of a methyl group at
the carbon atom adjacent to the aromatic group that is part of the
phenethylamine side chain provides approximately a 2- to 3-fold
improvement in potency in the EP300 HAT domain SPA assay. See
the supporting information for additional data.
(16) See the supporting information for additional information.
(17) Wilson, J. E.; Brucelle, F.; Levell, J. R. Amino amides as
P300/CBP HAT inhibitors and their preparation. Pat. Appl.
WO2019161162.
(18) The data in the text are for single compound PK experiments
with 17 while those in Table 3 are experiments with a cassette of at
least 3 compounds each. For comparison the single compound mouse
PK for compound 3 is as follows: 1mg/kg IV; 10 mg/kg PO;
clearance = 3.0 L/h/kg, Vss = 1.9 L/kg, T1/2 = 0.98 h, F% = 26;
AUC/dose = 90 h*mg/mL.
(19) Compound 17 was administered orally to eighteen male CD-1
mice. Plasma, brain, and CSF levels of compound 17 were then
determined at multiple time points. See the supporting information for
experimental details and additional data.
(20) Michaelides, M. R.; Kluge, A.; Patane, M.; Van Drie, J. H.;
Wang, C.; Hansen, T. M.; Risi, R. M.; Mantei, R.; Hertel, C.;
1
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Karukurichi, K.; Nesterov, A.; McElligott, F.; de Vries, P.; J. William
Langston, J. W.; Cole, P. A.; Marmorstein, R.; Liu, H.; Lasko, L.;
Bromberg, K. D.; Lai, A.; Kesick, E. A. Discovery of Spiro
Oxazolidinediones as Selective, Orally Bioavailable Inhibitors of
p300/CBP Histone Acetyltransferases. ACS Med. Chem. Lett. 2018, 9,
28-33.
(21) The structure of A-485 is shown below.
O
F
Me
HN
O
O
N
O
F
HN
N
F
O
F
Me
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ACS Medicinal Chemistry Letters
N
N
1
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Me
N
O
O
Me
H
Lead Optimization
H
N
N
Me
N
N
N
H
HN
CN
CN
Scaffold Replacement
Indole to Aminopyridine
3
17
Methyl Group
Favors active conformation
Lead EP300/CBP HAT inhibitor
- Low permiability & solubility
- hERG activity
>5-fold better EP300/CBP HAT activity
- Improved potency & solubility
- Low hERG activity
8
- in vivo efficacy @ 10 mg/kg PO BID
- in vivo efficacy @ 0.5 mg/kg PO BID
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