Identification of Imidazo[1,2- b]pyridazine Derivatives as Potent, Selective, and Orally Active Tyk2 JH2 Inhibitors

Article abstract of DOI:10.1021/acsmedchemlett.9b00035

In sharp contrast to a previously reported series of 6-anilino imidazopyridazine based Tyk2 JH2 ligands, 6-((2-oxo-N1-substituted-1,2-dihydropyridin-3-yl)amino)imidazo[1,2-b]pyridazine analogs were found to display dramatically improved metabolic stabilit

Full text of DOI:10.1021/acsmedchemlett.9b00035

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Letter
Identification of Imidazo[1,2-b]pyridazine derivatives as
Potent, Selective, and Orally Active Tyk2 JH2 Inhibitors
Chunjian Liu, James Lin, Ryan Moslin, John S Tokarski, Jodi K. Muckelbauer, ChiehYing Chang,
Jeffrey Tredup, Dianlin Xie, Hyunsoo Park, Peng Li, Dauh-Rurng Wu, Joann Strnad, Adriana
Zupa-Fernandez, Lihong Cheng, Charu Chaudhry, Jing Chen, Cliff Chen, Huadong Sun, Paul
Elzinga, Celia D'arienzo, Kathleen M. Gillooly, Tracy L. Taylor, Kim W. McIntyre, Luisa Salter-
Cid, Louis J Lombardo, Percy H Carter, Nelly Aranibar, James R. Burke, and David S. Weinstein
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.9b00035 • Publication Date (Web): 21 Feb 2019
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Lombardo, Louis; Bristol-Myers Squibb Research, Immunology Chemistry
Carter, Percy; BMS, R&D
Aranibar, Nelly; Bristol-Myers Squibb Pharmaceutical Research and
Development
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Burke, James; Bristol-Myers Squibb Pharmaceutical Research and
Development, Metabolism and Pharmacokinetic Department,
Pharmaceutical Candidate Optimization
Weinstein, David; Bristol Myers Squibb Co, Discovery Chemistry
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Identification of Imidazo[1,2-b]pyridazine derivatives as Potent,
Selective, and Orally Active Tyk2 JH2 Inhibitors
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Chunjian Liu*, James Lin, Ryan Moslin, John S. Tokarski, Jodi Muckelbauer, ChiehYing Chang,
Jeffrey Tredup, Dianlin Xie, Hyunsoo Park, Peng Li, Dauh-Rurng Wu, Joann Strnad, Adriana Zupa-
Fernandez, Lihong Cheng, Charu Chaudhry, Jing Chen, Cliff Chen, Huadong Sun, Paul Elzinga, Celia
D’arienzo, Kathleen Gillooly, Tracy L. Taylor, Kim W. McIntyre, Luisa Salter-Cid, Louis J. Lombardo,
Percy H. Carter, Nelly Aranibar, James R. Burke, and David S. Weinstein
Department Research & Development, Bristol-Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543, United States
KEYWORDS: Tyk2 JH2 inhibitor(s), Tyk2 JH2 ligand(s), Tyk2 pseudokinase inhibitor(s), Tyk2 pseudokinase ligand(s)
ABSTRACT: In sharp contrast to a previously reported series of 6-anilino imidazopyridazine based Tyk2 JH2 ligands, 6-((2-oxo-
N1-substituted-1,2-dihydropyridin-3-yl)amino)imidazo[1,2-b]pyridazine analogs were found to display dramatically improved
metabolic stability. The N1-substituent on 2-oxo-1,2-dihydropyridine ring can be a variety of alkyl, aryl and heteroaryl groups, but
among them, 2-pyridyl provided much enhanced Caco-2 permeability, attributed to its ability to form intramolecular hydrogen bonds.
Further SAR studies at the C3 position led to the identification of highly potent and selective Tyk2 JH2 inhibitor 6, which proved to
be highly effective in inhibiting IFNγ production in a rat pharmacodynamics model and fully efficacious in a rat adjuvant arthritis
model.
Tyrosine kinase 2 (Tyk2), a member of the Janus kinase
(JAK) family of non-receptor tyrosine kinases, regulates the
phosphorylation of Signal Transducer and Activation of
Transcription (STAT) proteins downstream of the receptors
for the p40-containing cytokines IL-12 and IL-23 as well as
Type I interferons such as IFNα, IFNβ, resulting in the
activation of STAT-dependent transcription and functional
responses specific for these receptors.1-3 These receptor
signaling pathways play key roles in the pathogenesis of
autoimmune and inflammatory diseases. IL-12 and IL-23
were found at high levels in lesional skin of psoriatic
patients,4-6 and the expression of these cytokines were shown
to decrease after various treatments that provide symptomatic
relief in psoriasis.7,8 Elevated serum IFNα levels were
observed in Systemic Lupus Erythematosus (SLE) patients,9
and the levels correlated to both disease activity and
severity.10 Inhibition of both IL-12 and IL-23 by targeting
their common p40 subunit with ustekinumab (Stelara®),
proved to be clinically effective for the treatment of
psoriasis11,12 and Crohn’s disease,13,14 and ustekinumab was
approved by FDA for the treatment of these diseases.
Targeting IFNα as a potential therapeutic solution to SLE was
also validated by the Phase IIb results from anifrolumab, a
human monoclonal antibody that binds to and blocks the
receptor for Type I interferons.15,16 Meanwhile, Tyk2 deficient
mice were reported to be resistant to collagen-induced arthritis
(CIA) and experimental autoimmune encephalomyelitis
(EAE).17,18 Thus, Tyk2 has been rationalized as a promising
target for developing orally active therapeutic agents for
autoimmune and inflammatory disorders19.
As the Janus kinase family is named after the two faced
Roman god Janus, the structures of Tyk2 and other Jak family
members feature dual kinase domains proximal to each other,
a catalytic kinase domain and a pseudokinase domain, also
called Jak homology 1 (JH1) and Jak homology 2 (JH2),
respectively. The Tyk2 JH2 is capable of binding adenosine
triphosphate (ATP), but it is catalytically incompetent.20
However, Tyk2 JH2 has been shown to play an important
regulatory role in Tyk2 function.21 Tyk2 JH1 inhibitors such
as 122 and 223 (Figure 1) have been reported. Due to the high
degree of homology among the JH1 of all Jak family
members, it is not surprising that 1 and 2 display only
moderate Tyk2 selectivity, as they also show significant
activities against Jak1-3.
In order to target the Tyk2 dependent signaling pathway
more selectively, we focused on Tyk2 JH2 due to its unique
structural difference in the binding pocket compared to JH1
and have recently disclosed the identification of Tyk2 JH2
ligand 3 (Figure 2) through a chemogenomic approach.24 This
Tyk2 JH2 ligand does not bind to Tyk2 JH1 and exhibits high
selectivity over other kinases including other Jak family
members. Moreover, 3 is effective in blocking the activation
of Tyk2 JH1. 6-Anilino imidazopyridazines (IZP) 4 represents
another chemotype of Tyk2 JH2 ligands that we have
preliminarily reported most recently.25 The structure-activity
rela tionship (SAR) for this series was investigated, but the
extremely poor metabolic stability remained a formidable
issue. For example, after 10 minutes of incubation of 4 in
human, rat, and mouse liver microsomes, the remaining 4 was
found to be only 11%, 14%, and 1%, respectively. Previous
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effort to address the metabolic stability issue led to 5, which
this assay. However, to our satisfaction, 6a displayed
significantly improved liver microsomal stability. After 10
minutes of incubation in human, rat, and mouse liver
microsomes, the remaining 6a was found to be 56%, 63%, and
10%, respectively, versus only 11%, 14%, and 1% for 4 (The
liver microsomal stability and Caco-2 data for all analogs are
arranged in Table I in the Supporting Information). More
encouragingly, when the N-methyl on the pyridone ring in 6a
was substituted with cyclopropyl, the liver microsomal
stability for 6b was further improved, with the recoveries now
being 88%, 71%, and 39%, respectively. Its Tyk2 JH2 binding
affinity and cellular activity were also improved to be
comparable to that for 4. Further more, Tyk2 JH2 ligand 6b
was found to be active in hWB assay with its IC50 being
determined to be 817 nM. Use of an aryl group such as para-
cyanophenyl on the pyridone resulted in 6c, which improved
the metabolic stability further to the incubation recoveries of
92%, 77%, and 71% from human, rat, and mouse liver
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2
3
4
5
6
7
8
displayed much improved liver microsomal stability with
99%, 76%, and 44% recoveries in human, rat, and mouse,
respectively. However, unfortunately, it showed very limited
permeability, indicated by its low Caco-2 value of 34 nm/sec,
and subsequently very limited exposure in vivo. Now, we
would like to report our modification of the 6-anilino IZP
series into 6-(2-oxo-N1-substituted-1,2-dihydropyridin-3-
yl)amino IZP, represented by 6. Tyk2 JH2 inhibitor 6 not only
dramatically improved the metabolic stability but it also
proved to be orally bioavailable, highly effective in inhibiting
IFN in rat, and fully efficacious in a rat adjuvant arthritis
(AA) model at a low dose (5 mg/kg, bid).
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CN
O
H2N
N
N
Cl
F
N
H
O
NH
N
Table 1. The SAR observed for R1 with 6a-m
O
N
F
OH
N
N
NH
H
N
1
2
6
N
3
HN
N
O
O
Figure 1. Literature Tyk2 JH1 inhibitors 1 and 2
HN
N
R1
N
NH
N
N
N
N
Tyk2 JH2
Ki (nM)
0.13
0.74
0.33
IFNα
hWB
6
compd
R1
S
N
N
H
N
IC50 (nM) IC50 (nM)
HN
4
6a
6b
NA
Me
cPr
96
614
131
ND
ND
817
O
NH
HN
O
SO2Me
NC
Me
6c
0.20
90
268
4
3
NH
HO
Me
NH
6d
0.07
111
811
N
N
6
N
HN
N
6e
6f
0.34
0.14
0.29
94
398
380
346
N
N
N
HN
N
F
O
O
N
HN
O
OH
MeO
F
F
140
148
HN
N
F
N
6g
OH
5
6
6h
6i
0.22
0.15
0.12
70
99
61
371
236
313
N
Figure 2. Tyk2 JH2 inhibitors 3-6
F
F
The much improved liver microsomal stability for
compound 5, compared to 4, is most likely due to its much
reduced cLogP of 1.99, calculated by ChemBioDraw Ultra
14.0, versus 3.80 for 4. It is well known that decreasing cLogP
can improve metabolic stability.26 The limited permeability
observed for 5 may be understandable considering that the
molecule carries five H-bond donors (three NH and two OH
groups). Searching for a moiety that can effectively reduce
cLogP without introducing too much polarity, we wondered if
the anilino group in 4 could be replaced with 2-oxo-N1-
N
F
6j
N
N
N
N
F
6k
6l
0.38
235
147
464
247
Me
Me
0.091
N
6m
0.48
135
340
N
N
Me
substituted-1,2-dihydropyridin-3-ylamino
functionality.
Thus, 6a, the calculated cLogP of which is 0.66, was
synthesized. The compound turned out to be approximately 6
fold less potent against Tyk2 JH2 compared to 4 based on
their Ki determinations (Table 1). It was also less potent by
about 6 fold than 4 in the IFNα stimulated luciferase reporter
assay in Kit225 T cells. The human whole blood (hWB)
activity for 6a was not obtained due to its poor solubility in
microsomes, respectively. Analog 6c displayed an hWB IC50
of 268 nM, 3 fold more active than what was observed for 6b,
although its Tyk2 JH2 affinity and cellular functional activity
were only slightly better.
A co-crystal structure of 6c bound to Tyk2 JH2 was
obtained,27 and the binding mode was revealed to be the same
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as that for a 6-anilino IZP ligand.25 Namely, 6c interacts with
Page 4 of 7
more permeable compared to 6f and 6g. The speculation was
confirmed by single-crystal X-ray analyses of 6e. Two
conformers resulted from rotations of the single bond between
the pyridine and pyridone rings were observed, and one of
them is shown in Figure 4. The dihedral angles between the
two heteroaryl rings is measured to be 34.8o, which is
significantly smaller than what (85.1o) was observed between
the cyanophenyl and pyridone rings in 6c. And, the speculated
intramolecular H-bonds are conceivable. The pyridyl and
pyridone rings in the other conformer29 are also more co-
planar (dihedral angle = 51.1o), though less significantly, than
the cyanophenyl and pyridone rings in 6c. The afore-
discussed intramolecular hydrogen bonding interactions in the
second conformer may be less significant, but the more co-
planar first conformer can certainly account for the much
higher Caco-2 permeability observed for 6e, considering the
two conformers will be in equilibrium in solution.
Metabolically, 6e is also more stable in the rodent liver
microsomes than 6f and 6g. On the basis of 6e, three
fluorinated 2”-pyridyl analogs 6h, 6i, and 6j were prepared.
All three compounds displayed very similar activity results to
that for 6e. Interestingly, only 6h and 6i remained highly
permeable as 6e. The Caco-2 of 59 nm/sec for 6j was more
like what was found for 6f and 6g. It can be rationalized that
due to the presence of 6’’-F on the pyridine in 6j, the pyridyl
and pyridone rings will be less co-planar and more polar (lack
of potential intramolecular hydrogen bonds), compared to 6h
and 6i. Among the other heteroaryls on the pyridone ring
examined, pyrimidyl and pyridazinyl were suitable to provide
activities and liver microsomal stability comparable to that for
6e, but the Caco-2 results for 6k and 6l were in the low to
moderate range. On the other hand, dimethylpyrazole derived
analog 6m was found to be highly permeable (Caco-2 = 142
nm/sec) in addition to showing good activities and liver
microsomal stability.
1
2
3
4
5
6
7
8
Tyk2 JH2 protein mainly through two hydrogen bond
networks (Figure 3). One occurs at the hinge region involving
hydrogen bonds between the C8 methylamino NH and the
carbonyl of Val690 and between N1 of the IZP core and the
NH of Val690. The other takes place near the gatekeeper
involving hydrogen bonds from the C3 amide carbonyl to the
NH of Lys642 and to the carbonyl of Glu688 through a
bridging water molecule. The pyridone ring is sandwiched
between the p-loop and Pro694, with the cyanophenyl
pointing to a solvent exposed area, which may mean a
relatively flat SAR for R1. It is noted that the cyanophenyl and
pyridone rings are almost perpendicular with the dihedral
angle between the two rings being 85.1o.
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hinge
Glu688
Val690
Ala671
water
Val697
Pro694
Thr687 -
“gatekeeper”
Lys642
Arg738
water
P-loop
Figure 3. Co-crystal structure of 6c bound to Tyk2 JH2
While 6c looked promising for its activities and metabolic
stability, its extremely low aqueous solubility (< 1 µg/mL at
pH 6.5 and 2 µg/mL at pH 1.0) was a concern. Replacement
of the cyano in 6c with a solubilizing group such as carbinol
(6d) led to significant loss of Caco-2 permeability. As a result,
we turned our focus to the exploration of N1-heteroaryl-2-
oxo-1,2-dihydropyridin-3-yl analogs. 2”-, 3”-, 4”-Pyridyl
analogs 6e, 6f, and 6g all provided Tyk2 JH2 enzymatic,
cellular, and hWB activities similar to what were obtained for
6c. The major differentiation among the three compounds
came from their Caco-2 permeability, with 6e (Caco-2 = 169
nm/sec) being significantly more permeable than 6f and 6g
(Caco-2 = 51 and 38 nm/sec, respectively). It should be
mentioned that the Caco-2 data were found to correlate very
well with in vivo exposures for the current series, and a
relatively high Caco-2 value was crucial for desired exposure.
In spite of knowing that the cyanophenyl and pyridone rings
were perpendicular in 6c in its co-crystal structure with Tyk2
JH2, we speculated that the 2”-pyridyl in 6e could be
significantly more co-planar to the pyridone ring, due to two
potential intramolecular hydrogen bonds: from the pyridyl
nitrogen to the proximal hydrogen on the pyridone ring and
from pyridone oxygen to the proximal hydrogen on the 2”-
pyridyl. Intramolecular hydrogen bonding interactions
involving aromatic C-H are known in literature.28 As a result,
the 2”-pyridyl nitrogen and the pyridone oxygen in 6e would
be shielded by the intramolecular hydrogen bonds and
therefore the molecule would be significantly less polar and
2.40 Å
2.45 Å
Figure 4. Single crystal structure of 6e
Table 2 presents the SAR results observed for R2 of the C3
amide side chain with R1 being fixed to be 2-pyridyl.
Replacement of the N-cyclopropyl in 6e with N-isopropyl
appeared to improve the Tyk2 JH2 binding affinity by 2 or 3
fold, but the cellular and hWB activities for 6n were slightly
less potent than that for 6e. The cyclobutyl analog 6o
displayed approximately the same potencies as 6e in all three
assays. A larger substitution such as 3-hydroxy-2,2-
dimethylpropyl was also well tolerated, as 6p was shown to
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be equipotent to 6e. The best finding for R2 was the
Compounds 6 and 6a-t were synthesized according to
1
2
3
4
5
6
7
8
enantiomeric (1R, 2S)-2-fluorocyclopropyl group, which
enhanced the Tyk2 JH2 affinity by 4 fold, as inhibitor 6
exhibited a Ki of 0.086 nM. The enhancement in enzymatic
potency led to the same level of improvement in its cellular
and hWB activities.
Scheme1, using
a
previously reported advanced
intermediate725 (Scheme 1). Hydrolysis of 7 provided IZP
carboxylic acid 8, which was then converted to carboxamide
9a-e
by
benzotriazole-1-
yloxytris(dimethylamino)phosphonium hexafluorophosphate
(BOP) promoted coupling reactions. Buchwald reactions of
9a-e with aminopyridone 10a-m, catalyzed by
Table 2. The SAR observed for R2 with 6e, 6n-p, and 6
tris(dibenzylideneacetone)dipalladium(0)/xantphos
or
NH
Pd(OAc)2/BrettPhos, followed by the removal of the p-
methoxybenzyl (PMB) protection group, gave rise to 6 and
6a-t.
Scheme 1a. Synthesis of 6, 6a-t
9
N
6
HN
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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N
3
N
O
O
N
HN
R2
N
PMB
PMB
N
N
N
N
N
N
N
N
a
b
Tyk2 JH2
Ki (nM)
0.34
0.13
0.26
IFNα
hWB
compd
R2
IC50 (nM) IC50 (nM)
Cl
Cl
CO2Et
CO2H
6e
6n
6o
cPr
iPr
94
153
60
382
750
384
8
7
cBu
NH
Me
Me
PMB
6p
OH
0.29
84
285
N
N
R
N
N
c
N
6
0.086
25
81
HN
N
F
S
Cl
N
O
O
HN
R2
O
HN
R2
N
R1
Table 3. The SAR observed for R1 with 6 and 6q-t
6, 6a-t
9a-e
NH
O
N
R1
NH2
6
N
N
3
N
HN
O
O
HN
10a-m
N
R1
aReagent and conditions: (a) LiOH, MeOH/THF, rt, 2 h, 97%; (b) R1NH2,
F
BOP, N, N-diisopropylethylamine, rt, 16 h, 55-97%; (c) i. 10a-m,
Tyk2 JH2
Ki (nM)
IFNα
hWB
tris(dibenzylideneacetone)dipalladium(0)/xantphos/Cs2CO3
Pd(OAc)2/BrettPhos/K2CO3, 1,4-dioxane, 80-125 C, 2-3 h, ii. HCl/1,4-
dioxane, CH2Cl2, rt, 30 min, 6-46% over 2 steps.
or
compd
R1
o
IC50 (nM) IC50 (nM)
6
0.086
0.035
25
26
81
85
N
Throughout the SAR studies, several compounds were
selected for pharmacokinetic (PK) studies, and it was found
that 6 exhibited the most desired PK profiles. The PK results
for 6 in mouse, rat, cyno, and dog are summarized in Table 4.
In brief, 6 displayed a low clearance rate of 7.8 mL/min/kg in
rat and moderate clearance rates of 16, 17, and 25 mL/min/kg
in mouse, cyno, and dog, respectively. It provided the highest
oral exposure and bioavailability (114%) in rat among the four
species examined. The bioavailability observed in mouse,
cyno, anddog were 86%, 46%, and 50%, respectively.
F
6q
N
6r
0.024
12
136
N
F
Me
6s
6t
0.015
0.018
22
41
90
63
N
N
Me
Me
N
N
Table 4a,b. PK profiles for 6 in mouse, rat, cyno, and dog
Combining (1R, 2S)-2-fluorocyclopropyl, the best group
identified for R2, with some of the preferred R1 from Table 1
prompted the synthesis of 6q-t (Table 3). As expected, these
compounds were highly potent inhibitors of Tyk2 JH2, with
their Ki values in the range of 0.015 to 0.035 nM. The Ki
values appeared to suggest that 6q-t would be somewhat more
potent inhibitors than 6, but in the cellular and hWB assays
they behaved very similarly to 6, with IFNα and hWB IC50
values in the ranges of 12 to 41 nM and 63 to 136 nM,
respectively. The liver microsomal stability for these
compounds were reasonable except for 6q. It was noticed that
all the (1R, 2S)-2-fluorocyclopropyl analogs showed reduced
Caco-2 permeability to some extent, compared to their
corresponding des-fluorocyclopropyl counterparts.
species
mouse rat
cyno
10
dog
10
Dose (PO) (mg/kg)
Cmax (µM)
10
15
19
16
86
10
9.4
57
1.8
11
0.93
8.0
25
AUC 0-24 h (µM*h)
CL (mL/min/kg)
F (%)
7.8
17
114
46
50
aVehicle: 5:5:90 TPGS:EtOH:PEG300; bIV dose: 2 mg/kg
Tyk2 JH2 inhibitor
6 was then evaluated in a
pharmacodynamic (PD) model to inhibit IL-12/IL-18 induced
IFN production. In this study, 6 was first administered to rats,
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and after one hour, the rats were challenged with IL-12.
Another hour later, they were further challenged with IL-18.
Five hours after drug administration, plasma samples were
collected and analyzed for IFN levels. As shown in Figure 5,
6 was effective in a dose dependent manner in this model,
inhibiting IL-12/IL-18 induced IFN production by 45% and
77% at doses of 1 and 10 mg/kg, respectively.
Page 6 of 7
imidazopyridazine based Tyk2 JH2 ligands to dramatically
improve metabolic stability. A variety of N1-heteroaryl
groups on the 2-oxo-1,2-dihydropyridin-3-yl were found
appropriate for Tyk2 JH2 activity, but it was 2-pyridyl that
provided the desired Caco-2 permeability due to its ability to
form intramolecular hydrogen bonds. Further SAR studies led
to the identification of highly potent and selective Tyk2 JH2
inhibitor 6. Compound 6 displayed good to excellent PK
profiles among the species of mouse, rat, monkey, and dog. It
was highly effective in a pharmacodynamic (PD) model to
inhibit IL-12/IL-18 induced IFN production in rat, and fully
efficacious in a preventive rat adjuvant arthritis (rat AA)
model at a dose of 5 mg/kg.
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45% inhibition
*
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77% inhibition
ASSOCIATED CONTENT
Supporting Information
*
200
The Supporting Information containing experimental procedures
and characterization for all final compounds, as well as
descriptions of in vitro and in vivo studies, is available free of
charge on the ACS Publications website.
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AUTHOR INFORMATION
Figure 5. Inhibitor 6 in the IL12 + IL18 induced IFN in rats (Vehicle:
5:5:90 TPGS:EtOH:PEG300)
Corresponding Author
*Tel: +1 609 466 5101; E-mail: chunjian.liu@bms.com.
2.5
Notes
Vehicle
The authors declare no competing financial interest.
2.0
2 mpk
ACKNOWLEDGMENT
The authors would like to acknowledge Richard Rampulla and
the BBRC DDS group for supply of intermediates.
5 mpk
1.5
10 mpk
1.0
REFERENCES
0.5
0.0
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Figure 6. Inhibitor 6 in the rat adjuvant arthritis model (bid dosing;
vehicle: 5:5:90 TPGS:EtOH:PEG300)
Compound 6 was also shown to be highly efficacious in a
rat adjuvant arthritis (rat AA) model. In this study, adjuvant
was given to rats on day zero for the rats to develop arthritis.
Meanwhile, 6 was dosed to the rats, twice a day, from day zero
to day twenty, during which period the rats’ paw volumes
were periodically measured. As seen in Figure 6, 6
demonstrated full efficacy to prevent the rats’ paw from
swelling at bid doses of 5 and 10 mg/kg.
It should be mentioned that 6 proved to be remarkably
selective over other kinases, displaying > 10,000 fold
selectivity for Tyk2 JH2 over a diverse panel of 230 kinases
that include Tyk2 JH1 and other Jak family members. HIPK4
is the only kinase, over which 6 showed a selectivity of only
480 fold. More specifically, 6 inhibited Jak1-3 with IC50
µ푀
values of > 2
activities of > 12.5 µM (IC50 values).
and displayed the Jak1-3 dependent cellular
In summary, a 2-oxo-1-substituted-1,2-dihydropyridin-3-
ylamino moiety was identified as a viable replacement for the
anilino group of a previously reported series of 6-anilino
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ACS Medicinal Chemistry Letters
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For Table of Contents Use Only
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N
Tyk2 JH2 Ki = 0.086 nM
IFN IC50 = 25 nM
hWB IC50 = 81 nM
effective in inhibiting IFN production in rats
efficacious in a rat adjuvant arthritis model
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