Discovery of N-(Indazol-3-yl)piperidine-4-carboxylic Acids as ROR?3t Allosteric Inhibitors for Autoimmune Diseases

Article abstract of DOI:10.1021/acsmedchemlett.9b00431

The clinical success of anti-IL-17 monoclonal antibodies (i.e., Cosentyx and Taltz) has validated Th17 pathway modulation for the treatment of autoimmune diseases. The nuclear hormone receptor RORγt is a master regulator of Th17 cells and affects the prod

Full text of DOI:10.1021/acsmedchemlett.9b00431

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Letter
Discovery of N-(indazol-3-yl)-piperidine-4-carboxylic acids
as ROR#t Allosteric Inhibitors for Autoimmune Diseases
Hongjun Zhang, Blair T. Lapointe, Neville Anthony, Rita Azevedo, Jos Cals, Craig C. Correll,
Matthew Daniels, Sujal Deshmukh, Hans van Eenenaam, Heidi Ferguson, Laxminarayan
G. Hegde, Willem Jan Karstens, John Maclean, J. Richard Miller, Lily Y. Moy, Vladimir
Simov, Sunil Nagpal, Arthur Oubrie, Rachel L. Palte, Gopal Parthasarathy, Nunzio
Sciammetta, Mario van der Stelt, Janice D. Woodhouse, B. Wesley Trotter, and Kenneth Barr
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.9b00431 • Publication Date (Web): 09 Jan 2020
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ACS Medicinal Chemistry Letters
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Discovery of N-(indazol-3-yl)-piperidine-4-carboxylic acids as RORγt
Allosteric Inhibitors for Autoimmune Diseases
Hongjun Zhang,*,§,1 Blair T. Lapointe,§,1 Neville Anthony,§,1 Rita Azevedo,§,2 Jos Cals,§,2 Craig C.
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,1
,2
,1
Δ
Correll, ,1 Matthew Daniels¶,1 Sujal Deshmukh, Hans van Eenenaam, Heidi Ferguson,
%
Π
%
,1
Laxminarayan G. Hegde,#,1 Willem Jan Karstens§, 2 John Maclean,Λ,1 J. Richard Miller, Lily Y.
Moy, Vladimir Simov, Sunil Nagpal, Arthur Oubrie, Rachel L. Palte, Gopal Parthasarathy,
Nunzio Sciammetta,§, 1 Mario van der Stelt,§, 2 Janice D. Woodhouse,#,1 B. Wesley Trotter,§, 1 Kenneth
Barr§, 1
#
,1
§, 1
,1
,2
, 1
, 3
$
#
%
$
$
§Medicinal Chemistry, %Discovery Biology, ¶Discovery Process Chemistry, ΠPharmacokinetics, Pharmacodynamics and
Drug Metabolism, ΔDiscovery Pharmaceutical Sciences, ΛModeling & Informatics, #In Vitro and In Vivo Pharmacology, and
$Computational and Structural Chemistry
1Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
2Merck Sharp & Dohme, Molenstraat 110, Oss 5342 CC, The Netherlands.
3Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
KEYWORDS: RORγt, IL-17, nuclear hormone receptor, allosteric inhibitor.
ABSTRACT The clinical success of anti-IL-17 monoclonal antibodies (i.e. Cosentyx® and Taltz®) has validated Th17 pathway
modulation for the treatment of autoimmune diseases. The nuclear hormone receptor RORγt is a master regulator of Th17 cells and
affects the production of a host of cytokines, including IL-17A, IL-17F, IL-22, IL-26 and GM-CSF. Substantial interest has been
spurred across both academia and industry to seek small molecules suitable for RORγt inhibition. A variety of RORγt inhibitors have
been reported in the past few years, the majority of which are orthosteric binders. Here we disclose the discovery and optimization
of a class of inhibitors, which bind differently to an allosteric binding pocket. Starting from a weakly active hit 1, a tool compound
14 was quickly identified which demonstrated superior potency, selectivity and off-target profile. Further optimization focused on
improving metabolic stability. Replacing the benzoic acid moiety with piperidinyl carboxylate, modifying the 4-aza-indazole core in
14 to 4-F-indazole and incorporating a key hydroxyl group led to the discovery of 25, which possesses exquisite potency and
selectivity, as well as an improved pharmacokinetic profile suitable for oral dosing.
T helper 17 (Th17) cells are a subset of effector T cells, which
play a key role in regulating immune response.1,2 Upon
stimulation, a unique pattern of cytokines are expressed and
secreted from Th17 cells, including IL-17A, IL-17F, IL-22, IL-
26, and GM-CSF. The Th17 pathway has been implicated in the
pathogenesis of many autoimmune diseases, including psoriasis
and psoriatic arthritis, rheumatoid arthritis (RA), inflammatory
bowel disease (IBD), and multiple sclerosis (MS).3 Recent
clinical success and FDA approval of several anti-IL-17
monoclonal antibodies such as secukinumab (CosentyxTM) and
Better and/or broader therapeutic outcomes could be attained by
simultaneously blocking multiple Th17-secreted cytokines.8,9
F
H
O
O
O
N
S
N
N
N
O
S
OH
CF3
CF3
O
N
N
N
N
N
CF3
O
O
T0901317
Genentech
Japan Tobacco
Cl
CF3
HO
O
O
O
N
O
S
N
O
N
O
F
O
CD3
O
N
H
ixekizumab (TaltzTM
) have validated the approach of
N
N
S
O
H2
N
CF3
O
Cl
modulating the Th17 pathway for the treatment of autoimmune
Biogen
Vitae/Allergan
GSK
diseases.4,5
COOH
The nuclear hormone receptor RORγt is a master regulator
for the differentiation and development of Th17 cells and
affects the production of IL-17 and several other Th17 related
cytokines.6,7 Accordingly, RORγt inhibition by small molecule
inhibitors might provide an alternative therapeutic approach to
IL-17 antibodies for the treatment of autoimmune diseases.7,8
O
N
H
N
F
N
Cl
N
N
(MRL-871)
O
O
O
COOH
CF3
Takeda
Merck
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Figure 1. Selected small molecule RORγt inhibitors
Emerging from
a
high-throughput screening (HTS)
1
2
3
4
5
6
7
8
campaign, several indazole derivatives represented by
arylsulfonamide 1 were identified as weakly active RORγt
inhibitors in a time-resolved fluorescence energy transfer (TR-
FRET) cofactor recruitment biochemical assay (IC50 = 958
nM).17 Our initial optimization effort began by exploring
different indazole nitrogen capping groups (Table 1). Switching
the sulfonamide moiety in 1 to a methylene group (2) boosted
binding affinity six folds. Conversion of sulfonamide to
carboxamide 3 further improved binding affinity and afforded
the first analog with single digit nanomolar activity (IC50 = 5
nM). Benzamide 3 also exhibited good activity in a cellular
chimeric RORgt-Gal4 report assay (Gal4) in HEK-293 cells
(IC50 = 400 nM).17
Intense interest has been garnered from both academia and
industry around identification of small molecule RORγt
inhibitors suitable for clinical development.10-13
Since the discovery of the non-selective RORγt inhibitor
T0901317,14 a variety of more selective, potent, and structurally
differentiating RORγt inhibitors have been reported as
exemplified in Figure 1.10-13,15-16 Several inhibitors have also
been advanced to clinical trials, through either oral or topical
administration for the treatment of various types of autoimmune
diseases.12,13 While the majority of these inhibitors bind to the
canonical orthosteric pocket,10-13 we recently disclosed the X-
ray co-crystal structures of several indazolyl carboxylic acids as
represented by MRL-871, which adopted a distinct binding
mode17,18 Two related classes of inhibitors were also reported
after our initial disclosure19,20 This kind of RORγt inhibitors
bind to a different allosteric pocket present in RORγt ligand
binding domain (LBD), which is different and distal to the
canonical ortherosteric pocket of many nuclear hormone
receptors including RORγt.17 Herein we describe in detail the
discovery and optimization of this class of inhibitors from a
weakly active hit to a highly potent and selective RORγt
inhibitor with much more favorable metabolic stability and off-
target profile.
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This encouraging result prompted us to explore a variety of
other amides. In general, analogs having bis-ortho substituents
(4, 5) attached to the benzoyl moiety were preferred over their
counterparts with mono-ortho or non-ortho substitution because
of their superior potency and chemical stability to amide
hydrolysis. Eventually 2-Cl-6-CF3 substituted analog
5
emerged not only by virtue of its potency, but also due to its
high stability under both basic and acidic conditions. At this
point, gratifyingly we also were able to obtain the co-crystal
structure of 5 (MRL-871),17 which not only revealed its unique
allosteric binding mode, but also provided useful structural
insight to guide our subsequent SAR exploration and
optimization.
We next began to investigate the effect of substitution around
the benzoic acid ring moiety. Since 4-F substitution on the
indazole core was slightly more favorable for cellular activity
(e.g. 6 vs 5), subsequent SAR exploration was carried out in the
same context (7-13). Ortho-substituents next to the carboxylate
moiety (F, Cl, or NH2) were generally detrimental for potency
(7-9). In contrast, the presence of ortho-OH further improved
both biochemical and cellular potency. Conversion of 10 into
its MeO-analog 11 led to a significant drop in potency.
Substitution at meta-position was also briefly explored (12, 13),
with meta-fluoro substitution showing marginal benefit.
Table 1. SAR exploration from arylsulfonamide hit 1
COOH
COOH
R3
o
m
Y
N
N
Cl
R2
N
N
O
S
X
O
Cl
R1
1
Weakly active hit
Gal4
aIC50 (nM)a
Fret
IC50 (nM)
X
Y
R1
R2
R3
NAb
SO2
CH2
1
2
CH Cl
CH Cl
Cl
Cl
H
H
958
158
3116
400
393
127
72
Table 2. Indazole core modification
3
4
CO
CO
CH Cl
CH Cl
Cl
H
H
5
Gal4
Fret
OiPr
CF3
clogP
5.4
48
IC50 (nM)a
IC50 (nM)a
5
6
CO
CO
CH Cl
C-F Cl
H
H
2
3
COOH
F
N
CF3
CF3
14
15
N
N
6
6
90
99
4
N
Y
7
CO
CO
CO
CO
CO
C-F Cl
C-F Cl
C-F Cl
C-F Cl
C-F Cl
o-F
13
84
93
3
131
610
687
17
3
X
Cl
Z
6
N
CF3
8
o-Cl
O
N
5.3
N
CF3
CF3 o-NH2
9
CF3
10
11
o-OH
N
N
16
17
18
9
177
187
4.2
4.9
N
N
CF3
o-OMe 586
NA
CF3
CF3
12
13
CO
CO
C-F Cl
C-F Cl
m-F
3
34
N
m-Cl
10
190
N
aIC50 values are the mean of at least two runs. Potency values represent for
N=2 data differed by less than 3 fold, and otherwise additional replicae were
collected..bNA stands for not tested.
aIC50 values are the mean of at least two runs.
With potent analogs such as 10 and 12 (MRL-299)17 in hand,
one of our goals early on was to identify a tool compound with
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sufficient potency, metabolic stability, and favorable off-target
carboxylate into other typical acid bio-isosteres, such as
tetrazole or acyl-sulfonamide groups led to significant loss of
potency.23 Another tactic to mitigate glucuronidation is to
introduce steric hindrance next to the carboxylate moiety,24 but
none of the o-substituents ( i.e. 8-9, 11 ) except OH (10) was
not tolerated in our case as noted previously. Unfortunately,
compound 10 also showed poor metabolic stability.
1
2
3
4
5
6
7
8
profile suitable for preliminary in vitro and in vivo proof-of-
biology studies. For this purpose, the compounds in Table 2
were prepared. Incorporation of a nitrogen atom into either the
4 or 6 position of the core was tolerated with minimal loss of
activity (14-16). However, nitrogen substitution at the 6
position of the indazole core (15) led to notable CYP inhibition
(CYP3A4 IC50 = 4.8 μM). Aza-indole analog 17 was also
tolerated with a slight decrease in potency relative to 14. Aza-
indazole analog 14 (MRL-248)21 was profiled in a Eurofins
panel of counter screening at a concentration of 10 uM against
a panel of 108 additional kinases, receptors, transporters, and
nuclear receptors and showed only weak activity again one
target in the panel (PPARγ, IC50 = 2 uM ). In contrast,
compound 12 showed 9 hits with >50% inhibition under the
same conditions. Compound 14 also showed no appreciable
activity against a panel of related nuclear hormone receptors.21
In addition, sufficient oral exposure could be achieved with 14
in a high dose mouse pharmacokinetic study. Based on its PK
and selectivity profile, compound 14 was chosen as a tool
compound and utilized extensively in various in vitro and in
vivo studies.21, 22
At this stage, we envisioned a strategy of saturating the
benzoic acid ring moiety, and prepared the compounds in Table
3. Piperidyl carboxylate 18 showed much weak activity, while
its cyclohexenyl counterpart 19 displayed modest activity.
Hydrogenation of alkene in 19 gave both cis- and trans- isomer,
but neither of them led to any improvement. Gratifyingly,
switching to 4-F-indazole core (20) exhibited significant gain in
potency compared to the corresponding analog with the
azaindazole core (18). Cyclohexenyl analogs (21) also
benefited greatly from the same core change.
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25
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Next, our efforts then focused on incorporation of additional
polar substituents to reduce the lipophilicity and improve other
ancillary properties of these analogs.25 Introduction of β-OH
substitution next to the carboxylate was quite encouraging (22-
24). Although racemic cis-isomer 22 was less potent, one
enantiomer of its corresponding trans-isomer (24 vs 23)
displayed better biochemical and cellular activity than 20.
Later, we also found that 2-Cl-6-(cyclopropyl)-benzoyl moiety
(25) imparted additional gain in potency compared with 2-Cl-
6-CF3 benzoyl (24) as the indazole capping group.
Table 3. SAR of benzoic acid replacement
Fret
Gal4
R1
R2
Y
N
IC50 (nM)a IC50 (nM)a
4
Y
R2
N
Compound 25 was selected for broad profiling and
demonstrated a much more favorable overall profile compared
with our tool compound 14 (Figure 2). Besides excellent
binding and cellular activity, 25 also exhibited very good
potency in a Th17 differentiation/IL17A production assays in
primary human peripheral blood mononuclear cells (PBMCs).17
Furthermore, 25 was metabolically more stable than 14, and
demonstrated improved in vivo pharmacokinetic profile in both
rat and dog PK studies. In addition, 25 showed a clean off-target
profile in Eurofins Panlabs panel (Supporting information).
Consistent with its lower clogP and higher Fsp3, 25 also shows
improvement in physiochemical properties (e.g. solubility @
pH=2).26
COOH
3
Cl
18
19
CF3
461
3766
N
N
O
R1
COOH
N
CF3
CF3
76
7
1302
300
racemic
COOH
20 C-F
N
COOH
21 C-F
22 C-F
CF3
CF3
4
107
racemic
COOH
OH
39
1188
racemic
N
COOH
OH
23 C-F
CF3
CF3
51
2035
N
(3R, 4S)
COOH
OH
24 C-F
25 C-F
2
1
53
49
(3S, 4R)
N
COOH
OH
(3S, 4R)
N
aIC50 values are the mean of at least two runs.
Our next goal focused on improving the metabolic stability
of 14 while maintaining its favorable potency, selectivity and
off-target profile. Met ID studies of incubating 14 in
hepatocytes revealed acyl-glucuronidation as one of its major
clearance mechanisms. Unfortunately, several attempts to
overcome this metabolism pathway by converting the
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COOH
COOH
Compound 14
plasma
concentration
OH
N
1
2
3
4
5
6
7
8
F
N
Dose (mpk)
F
N
N
Cl
Cl
N
N
(µM)
0.18
0.73
4.1
51
254
O
O
1
3
10
30
100
CF3
14
25
2.0
1.5
1.0
0.5
0.0
Potency
Fret IC50 (nM)
Gal4 IC50 (nM)
PBMC IC50 (nM)
6
1
49
13
90
33
17%
9
10
11
12
13
14
15
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17
18
19
20
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25
26
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50
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50%
In vivo PK
Rat: Cl (ml/min/Kg), T1/2 (h),
Vd (L/kg), F%
Dog: Cl (ml/min/Kg), T1/2 (h),
Vd (L/kg), F%
76, 0.4,
13, 3.7,
*
74%
0.8, 16%
4.5, 1.4,
0.4, 45%
0.6, 35%
1.4, 3.1,
0.3, 65%
69%
*
85%
*
*
Other properties
PPB(rat, dog)
98.7%, 98.7% 98.7%, 99.7%
clogP
Fsp3
4.6
2.7
0.35
0.05
Veh
1
3
10
30
100
<2, 147
28, 153
Solubility ( M) @ pH=2 and 7

Compound 14 (mg/kg)
Figure 2. Overall profile of 25 vs 14
Gratifyingly, we also obtained an X-ray co-crystal structure
of 25 bound to RORγt ligand binding domain (LBD) (Figure 3).
The carboxylate group forms several H-bond interactions with
RORγt backbone or residues, including Phe498, Ala497 and
Gln329. The 2-Cl-6-(cyclopropyl)-phenyl group is positioned
nearly perpendicular to the plane of the indazole core. The β-
hydroxy group of the piperidine ring forms an intramolecular
H-bond with the carboxylate moiety, as well as Phe498.
Figure 4. Dose-dependent in vivo inhibition of Bcl-xL expression
by 14. The data shown in the figure refer to Mean ± SEM values.
In summary, a class of N-(indazol-3-yl)-piperidine-4-
carboxylic acids was discovered as highly potent and selective
RORγt allosteric inhibitors. From weakly active hit
arylsulfonamide 1, replacing the sulfonamide with bis-ortho-
substituted benzamide and switching the central core from
indazole to 4-aza-indazole led to the discovery of early tool
compound 14. Despite its good potency and selectivity,
compound 14 exhibited less optimal metabolic stability.
Subsequent optimization featured saturation of the benzoic acid
moiety in order to slow down metabolic clearance. The initially
significant potency loss arising from replacement of the benzoic
acid moiety with 4-piperidinyl carboxylic acid could be
regained by switching from 4-aza-indazole core to 4-F-indazole
core. Incorporation of a β-hydroxyl group on the piperidine and
swapping of ortho substituent from CF3 to cyclopropyl
culminated in the discovery of 25. In addition to its superior
potency, selectivity, and favorable off-target profile, compound
25 exhibited much improved in vivo metabolic stability across
species. Furthermore, compound 14 was evaluated in an acute
PD model where it demonstrated a robust dose-dependent
inhibition of Bcl-xL expression in thymocytes, providing
valuable proof of biology for this class of allosteric inhibitors.
Figure 3. Co-crystal structure of 25 with RORγt LBD domain
Prior to discovery of 25, compound 14 was chosen for an in
vivo study in an acute mouse pharmacodynamic (PD) model
(Figure 4).27 Inhibition of RORγt blocks the expression of Bcl-
xL in thymocytes. C57BL/6 mice received a single dose of
compound 14 and were sacrificed after 2h. Both plasma
concentration of 14 and Bcl-xL expression levels in thymocyte
were measured. In consistent with pharmacologically induced
RORγt inhibition, compound 14 inhibited in vivo Bcl-xL
expression in a robust dose dependent manner (IC50 = 0.71 μM).
ASSOCIATED CONTENT
Supporting Information
Synthetic procedures and analytical data for representative
compounds, protocols for biological assays and Bcl-xL PD model,
X-ray statistics for 25 RORγt binding to ligand binding domain,
and data of panlabs profiling of 25.
The Supporting Information is available free of charge on the ACS
Publications website.
Accession Codes
The PDB code for 25 is 6UCG.
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receptors ROR alpha and ROR gamma. Immunity
AUTHOR INFORMATION
Corresponding Author
1
2
3
4
5
6
7
8
2008, 28, 29-39.
(8) (8) Isono, F.; Fujita-Sato, S.; Ito, S. Inhibiting
RORγt/Th17 axis for autoimmune disorders. Drug
Discov. Today 2014, 19, 1205-1211.
*Phone: 857-529-3656. Email: david.zhang@cerevel.com.
ORCID
Hongjun Zhang: 0000-0002-1136-6142
(9) Yang, J.; Sundrud, M. S.; Skepner, J.;Yamagata, T.
Targeting Th17 cells in autoimmune diseases. Trends
Pharmacol. Sci. 2014, 35, 493-500.
Notes
The authors declare no competing financial interest.
(10) Fauber, B. P.; Magnuson, S. Modulators of the nuclear
receptor retinoic acid receptor-related orphan receptor-
γ (RORγ or RORc). J. Med. Chem. 2014, 57, 5871-
5892.
(11) Kumar, S.; Sachchidanand; Sharma, R.; Desai, R. C.
Combating autoimmune diseases with retinoic acid
receptor-related orphan receptor-γ (RORγ or RORc)
inhibitors: hits and misses. J. Med. Chem. 2018, 61,
10976-10995.
ACKNOWLEDGMENT
9
We thank Drs. Tom D. Aicher, Peter L. Toogood, and Xiao Hu
(Lycera Corp, Michigan, USA) for helpful discussion. We also
thank Drs Josep Sauri and Yuan Jiang for assisting some analytical
data collection (13C NMR and HRMS data). In addition, we thank
Drs. Dongshan Zhang, Xiaobang Duan and Richard Thomas
Beresis (Chempartner, Shanghai, China) for chemical synthesis of
some of the compounds discussed in this article.
10
11
12
13
14
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17
18
19
20
21
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23
24
25
26
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(12) Cyr, P.; Bronner, S. M.; Crawford, J. J. Recent progress
on nuclear receptor RORγ modulators. Bioorg. Med.
Chem. Lett. 2016, 26, 4387-4393.
(13) Bronner, S. M.; Zbieg, J. R.; Crawford, J. J. RORγ
antagonists and inverse agonists: a patent review.
Expert Opin. Ther. Pat. 2017, 27, 101-112.
(14) Kumar, N.; Solt, L. A.; Conkright, J. J.; Wang, Y.;
Istrate, M. A.; Busby, S. A.; Garcia-Ordonez, R. D.;
Burris, T. P.; Griffin, P. R. The benzenesulfoamide
ABBREVIATIONS
ROR: retinoid-related orphan receptor; TR-FRET: time-resolved
fluorescence energy transfer; PBMC: peripheral blood
mononuclear cell; Bcl-xL: B-cell lymphoma-extra large; LBD:
ligand binding domain; Met-ID: metabolite identification.
REFERENCES
T0901317
[N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-
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Discovery of N-(indazol-3-yl)-piperidine-4-carboxylic acids as
RORγt Allosteric Inhibitors for Autoimmune Diseases
Hongjun Zhang,*,§,1 Blair T. Lapointe,§,1 Neville Anthony,§,1 Rita Azevedo,§,2 Jos Cals,§,2 Craig
,1
,2
,1
Δ
C. Correll, ,1 Matthew Daniels¶,1 Sujal Deshmukh, Hans van Eenenaam, Heidi Ferguson,
%
Π
%
,1
Laxminarayan G. Hegde,#,1 Willem Jan Karstens§, 2 John Maclean,Λ,1 J. Richard Miller, Lily Y.
#
Moy, Vladimir Simov, Sunil Nagpal, Arthur Oubrie, Rachel L. Palte, , 1 Gopal
,1
§, 1
,1
,2
#
%
$
$
Parthasarathy, , 3 Nunzio Sciammetta,§, 1 Mario van der Stelt,§, 2 Janice D. Woodhouse,#,1 B.
$
Wesley Trotter,§, 1 Kenneth Barr§, 1
§Medicinal Chemistry, %Discovery Biology, ¶Discovery Process Chemistry, ΠPharmacokinetics, Pharmacodynamics
and Drug Metabolism, ΔDiscovery Pharmaceutical Sciences, ΛModeling & Informatics, #In Vitro and In Vivo
Pharmacology, and $Computational and Structural Chemistry
1Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
2Merck Sharp & Dohme, Molenstraat 110, Oss 5342 CC, The Netherlands.
3Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486 USA.
COOH
COOH
COOH
OH
F
N
F
N
N
N
N
Cl
Cl
N
N
N
O
S
O
Cl
O
O
Cl
CF3
14
25
1
Tool compound
Lead molecule
Weakly active hit
FretT IC50: 1 nM
hPBMC IC50: 13 nM
rat PK: Cl/Clunbound
13/1000 ml/min/kg
clogP: 2.7
Fret IC50: 6 nM
hPBMC IC50: 33 nM
rat PK: Cl/Clunboud
76/5846 ml/min/kg
clogP: 4.6
Fret IC50: 958 nM
Fsp3: 0.35
Fsp3: 0.05
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