Discovery of novel 2,3-diarylfuro[2,3-b]pyridin-4-amines as potent and selective inhibitors of Lck: Synthesis, SAR, and pharmacokinetic properties

Article abstract of DOI:10.1016/j.bmcl.2007.01.048

2,3-Diarylfuro[2,3-b]pyridine-4-amines are a novel class of potent and selective inhibitors of Lck. The discovery, synthesis, and structure activity relationships of this series of inhibitors are reported. The most promising compounds were also profiled t

Full text of DOI:10.1016/j.bmcl.2007.01.048

Bioorganic & Medicinal Chemistry Letters 17 (2007) 2299–2304
Discovery of novel 2,3-diarylfuro[2,3-b]pyridin-4-amines as potent
and selective inhibitors of Lck: Synthesis, SAR,
and pharmacokinetic properties
Matthew W. Martin,a,* John Newcomb,b Joseph J. Nunes,a Jean E. Bemis,a
David C. McGowan,a Ryan D. White,a John L. Buchanan,a Erin F. DiMauro,a
Christina Boucher,b Theodore Faust,b Faye Hsieh,d Xin Huang,c Josie H. Lee,b
Stephen Schneider,b Susan M. Turcib and Xiaotian Zhuc
aDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, MA 02139, USA
bDepartment of HTS and Molecular Pharmacology, Amgen Inc., One Kendall Square, Building 1000, Cambridge, MA 02139,USA
cDepartment of Molecular Structure, Amgen Inc., One Kendall Square, Building 1000, Cambridge, MA 02139, USA
dDepartment of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
Received 20 November 2006; revised 12 January 2007; accepted 12 January 2007
Available online 24 January 2007
Abstract—2,3-Diarylfuro[2,3-b]pyridine-4-amines are a novel class of potent and selective inhibitors of Lck. The discovery, synthe-
sis, and structure activity relationships of this series of inhibitors are reported. The most promising compounds were also profiled to
deduce their pharmacokinetic properties.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The lymphocyte-specific kinase (Lck) is a cytoplasmic
tyrosine kinase of the Src family expressed in T cells
and natural killer cells.1 Genetic evidence in both mice
and humans demonstrates that Lck activity is important
for signaling mediated by the T cell receptor (TCR) and
leads to normal T cell development and activation.2
These findings suggest that a small molecule inhibitor
of Lck could be a useful immunosuppressive for the
treatment of T cell-mediated autoimmune and inflam-
matory disorders and/or organ transplant rejection.
(piperazin-1-yl)ethyl)furo-[2,3-d]pyrimidin-4-amine
(compound 1, Fig. 1), as potent and selective inhibitors
of Lck and T cell proliferation.5 X-ray crystallization
studies of 1 bound to Lck6 revealed that the pyrimidine
core in 1 binds to the linker region through two hydro-
gen bonds (Fig. 2): methionine 319 donates a backbone
NH to the N1 pyrimidine acceptor and the carbonyl
from Glu 317 accepts the CH in the 2-position.7 Inter-
estingly, the N3 of the pyrimidine ring does not appear
to be engaged in any H-bond interactions.
A number of groups, including our own,3 have previous-
ly reported the synthesis and characterization of Lck
kinase inhibitors.4 Potent and orally bioavailable Lck
inhibitors have also been demonstrated to have inhibito-
ry activities in vivo in several models of T cell-dependent
immune responses.3,4d,e
Based on this observation, we theorized that removal of
the N3 nitrogen should provide compounds (furanopyri-
dines) with similar biological activity, and possibly
We recently described the discovery of a novel series of
furanopyrimidines, exemplified by 5,6-diphenyl-N-(2-
Keywords: Lck inhibitor; Kinase inhibitor.
*
Corresponding author. Tel.: +1 617 444 5013; fax: +1 617 621
3908; e-mail: matmarti@amgen.com
Figure 1. Structure and activity of furanopyrimidine 1.
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.01.048

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M. W. Martin et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2299–2304
amination.10 Compound 7 was then reacted with triflu-
oroacetic acid to effect N-Boc deprotection and afford
furanopyridine 8.
Compounds 6 and 8 were tested for inhibitory activity
against Lck in a homogeneous time-resolved fluorescent
(HTRF) kinase assay. For the purposes of determining
kinase selectivity, the compounds were also screened
against the related kinases KDR, Ack1, and JAK3.11
Cellular activity was measured by testing the com-
pounds for the inhibition of T cell receptor mediated
IL-2 production in human T cells as well as for the inhi-
bition of T cell activation in a human mixed lymphocyte
reaction.12
The initial data for this novel series of inhibitors shown
in Table 1. While neither compound exhibited the
desired selectivity profile, the nature of the amine in
the 4-position proved to be critical. Whereas the 4-(2-
piperazin-1-yl)ethylamine derivative 8 exhibited modest
potency (0.21 lM), the (S)-(tetrahydrofuran-2-yl)me-
thylamine derivative 6 was significantly less potent
(2.1 lM). This is in sharp contrast to the related furano-
pyrimidines, where many more groups were tolerated.5
To better understand this phenomenon, we obtained a
co-crystal structure of furanopyridine 8 with Lck.
Figure 2. X-ray structure of furanopyrimidine 1 bound to Lck.
improved selectivity. Herein, we describe the synthesis,
structure activity relationships, and pharmacokinetic
properties of a series of substituted 2,3-diarylfuro[2,3-
b]pyridin-4-amines, a new class of small molecule inhib-
itors of Lck.8
As shown in Figure 3,13 furanopyridine 8 binds to Lck in
a manner similar to furanopyrimidine 1, with the pyridine
nitrogen accepting a backbone NH from Met 319 and
the carbonyl from Glu 317 accepting the CH in the 6-po-
sition of the pyridine ring. The 2-phenyl group points
out of the enzyme toward solvent, providing an area
to introduce polar solubilizing groups for better cell pen-
etration. Interestingly, both 1 and 8 exhibit potency de-
spite not filling the hydrophobic pocket.14 In addition,
the piperidine ring fills the smaller pocket adjacent to
the ribose-binding pocket allowing for a key interaction
between the piperidine NH and Asn 369. The inability
of furanopyridine 6 to make this interaction (it has no
NH to donate) could explain its decreased potency
relative to 8.
We developed a concise route for the construction of the
desired 2,3-diarylfuro[2,3-b]pyridin-4-amines. As illus-
trated in Scheme 1, the key step was the use of Balme’s
procedure for the synthesis of furo[2,3-b]pyridones.9 In
this reaction, iodopyridone 3 was treated sequentially
with phenylacetylene and iodobenzene to afford furano-
pyridone 4 in good yield via a one-pot coupling–cycliza-
tion–deprotection process. Subsequent chlorination with
phosphorus oxychloride provided 4-chlorofuranopyri-
dine 5, which was converted to the 2,3-diarylfuro[2,3-
b]pyridin-4-amines 6 and 7 via a palladium-catalyzed
With these initial data and structural information in
hand, we carried out structure–activity relationship
studies designed to identify the substituents for
increased potency, selectivity, and optimal pharmacoki-
netic properties. Our work focused on two areas: substi-
tution on the 2-phenyl ring and optimization of the
amine side chain in the 4-position. To construct the
desired compounds, we used the synthetic plan outlined
in Scheme 2.
The new route was based on a revised version of the
chemistry outlined in Scheme 1. Substituting 4-(ben-
zyloxy)phenylacetylene for phenylacetylene in the key
coupling–cyclization–deprotection step afforded key
intermediate furanopyridone 9. Palladium-catalyzed
hydrogenation and subsequent chlorination with oxa-
lyl chloride afforded 4-chlorofuranopyridine 10, which
contained two handles for examining the desired sub-
stitutions. As in the original route, palladium-cata-
lyzed amination introduced the side chain in the
Scheme 1. Synthesis of 2,3-diphenylfuro[2,3-b]pyridin-4-amines. Reagents
and conditions: (a) phenylacetylene, PdCl2(PPh3)2, CuI, Et3N,
CH3CN, 60 ꢁC, 24 h then PhI, 60 ꢁC, 24 h, 63%; (b) POCl3, 110 ꢁC,
18 h, 57%; (c) RNH2, Pd(OAc)2, BINAP, K2CO3, toluene, 130 ꢁC,
18 h; (d) CF3CO2H, CH2Cl2, rt, 2.5 h, 68% (two steps).

M. W. Martin et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2299–2304
Table 1. Initial furanopyridine SAR (IC50, lM)a
2301
Compound
R
Lck
2.1
KDR
4.2
Ack1
0.11
JAK3
0.026
IL-2b
5.2
huMLRc
6
4.0
8
0.21
0.36
0.42
0.14
1.2
0.62
a IC50 values are means of two or more separate determinations, in duplicate.
b IL-2: anti-CD3/CD28-induced T cell IL-2 secretion assay.
c huMLR: human Mixed Lymphocyte Reaction.
4-position (compound 11). Subsequent alkylation of
the phenol and deprotection afforded the desired com-
pounds 12.
Table 2 summarizes our results for the introduction of
solubilizing groups on the 2-phenyl group. In general,
the addition of the basic amine side chains increased
enzyme potency four- to ten-fold relative to 8.
Selectivity against KDR, Ack1, and JAK3 remained
unchanged, ranging from two- to five-fold over Lck.
Consistent with what was observed for 8, all compounds
experienced an approximately five- to ten-fold shift
(relative to the enzyme IC50) when tested for cell activity
in the IL-2 secretion assay. A much smaller shift
(ꢀ2-fold) was observed when the compounds were test-
ed in the huMLR, with compounds 13, 15, 16, and 17
exhibiting IC50 values between 20 and 60 nM.
Figure 3. X-ray structure of furanopyridine 8 bound to Lck.
Having established the benefits of substituting the
2-phenyl ring, we next explored the SAR of the 4-amino
side chain. We were interested in cyclic amines that
could engage Asn 369 and provide compounds with
increased enzyme and cell potency relative to piperidine
derivative 17. As shown in Table 3, replacing the piper-
azine with aromatic heterocycles led to a decrease in
potency in all examples tested. Presumably, none of
these compounds can form favorable H-bond interac-
tions with Asn 369.
We also examined the pharmacokinetic properties of a
number of cell potent compounds. Compounds 8, 13,
15, 16, and 17 were tested for microsomal stability
and dosed iv in Sprague–Dawley rats (Table 4). Com-
pound 8 (at 0.62 lM, the least potent in cells) showed
moderate clearance (1.2 L/h/kg) and a short half-life
(1.5 h). In contrast, compounds 13, 15, 16, and 17,
all of which exhibited promising cellular activity, each
had undesirable PK properties. All four compounds
were cleared at a rate higher than hepatic blood flow
(ꢀ8–11 L/h/kg) and showed a correspondingly high
volume of distribution (7–122 L/kg). Furthermore, in vi-
tro microsomal clearance was not predictive of in vivo
stability.15 Whereas compounds 15 and 16 exhibited
Scheme 2. Modified synthesis of 2,3-diphenylfuro[2,3-b]pyridin-4-
amines. Reagents and conditions: (a) 4-(benzyloxy)phenylacetylene,
PdCl2(PPh3)2, CuI, Et3N, CH3CN, 60 ꢁC, 24 h then PhI, 60 ꢁC, 24 h,
61–62%; (b) H2 (g), Pd/C, EtOAc–CH2Cl2, rt, 16 h, 71–86%; (c)
(COCl)2, cat. DMF, CHCl3, reflux, 2 h, 65%; (d) R1NH2, Pd(OAc)2,
BINAP, K2CO3, toluene, 130 ꢁC, 18 h, 46–60%; (e) ClCH2CH2NR2,
Cs2CO3, DMF, 85 ꢁC, 16 h; (f) CF3CO2H, CH2Cl2, 0 ꢁC to rt, 2 h, 82–
91% (two steps).

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M. W. Martin et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2299–2304
Table 2. SAR: variations on the 6-phenyl group (IC50, lM)a
Compound
R
Lck
0.21
KDR
0.36
Ack1
0.42
JAK3
0.14
IL-2b
1.2
huMLRc
0.62
8
H
13
14
15
16
17
0.022
0.054
0.030
0.019
0.029
0.057
0.21
0.15
0.17
0.084
0.18
0.12
0.032
0.11
0.13
0.65
0.47
0.25
0.51
0.014
0.17
0.16
0.025
0.044
0.071
0.057
0.018
0.061
0.067
0.10
a IC50 values are means of two or more separate determinations, in duplicate.
b IL-2: Anti-CD3/CD28-induced T cell IL-2 secretion assay.
c huMLR: human mixed lymphocyte reaction.
Table 3. SAR: variations on the 4-amino side chain (IC50, lM)a
Table 4. Pharmacokinetic parameters following iv Dose in Sprague-
Dawley Ratsa,b
clogPd
c
Compound CL
Vss
t1/2 (h) CLint
(L/h/kg) (L/kg)
(lL/min/mg)
8
13
15
16
17
1.2
7.7
2.3
4.7
7.2
122
60
1.5
5.3
0.8
3.1
4.7
137
4.7
4.8
4.4
6.6
6.0
<5
100
120
50
11.5
34.1
11.3
Compound
R
Lck
KDR
0.10
Ack1
0.12
JAK3
0.071
a n = 3 animals per study.
b Dosed at 1 mg/kg as a solution in DMSO.
17
0.029
c In vitro intrinsic clearance after incubation with rat liver microsomes.
Compound concentration = 1 lM, microsomal protein = 0.25 mg/
mL.
18
19
20
1.6
4.7
0.18
0.020
0.93
0.080
0.037
1.4
d Determined using ACDLabs 8.0.
0.17
0.37
In summary, we have reported the discovery of a novel
class of 2,3-diarylfuro[2,3-b]pyridin-4-amines that are
potent and selective inhibitors of Lck. These compounds
show promising cellular activity when tested in a human
MLR and in an anti-CD3/CD28-induced IL-2 secretion
assay. Despite non-optimal pharmacokinetic properties,
these initial compounds show the potential of furano-
pyridines as a new class of Lck inhibitors. Future work
will aim to improve the potency and pharmacokinetic
properties with the hope of identifying compounds suit-
able for in vivo studies.
0.38
1.7
a IC50 values are means of two or more separate determinations, in
duplicate.
high clearance both in vivo and in vitro, compounds 13
and 17 showed promising in vitro clearance but high
rates of in vivo clearance. The observed PK properties
are best interpreted in the context of the clogP for each
of the compounds.16 With the exception of compound
15, the clogP increased with the introduction of the
polar amine side chains, with the high clogP values
of 16 and 17 accounting for the large clearance
values.17
Acknowledgments
We are grateful to our colleagues Linda Epstein, Yan
Gu, Paul Rose, and Huilin Zhao for Lck protein expres-

M. W. Martin et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2299–2304
2303
5. DiMauro, E. F.; Newcomb, J.; Nunes, J. J.; Bemis, J. E.;
Boucher, C.; Buchanan, J. L.; Buckner, W. H.; Chang, A.;
Faust, T.; Hsieh, F.; Huang, X.; Lee, J. H.; Marshall, T.
L.; Martin, M. W.; McGowan, D. C.; Schneider, S.; Turci,
S. M.; White, R. D.; Zhu, X. Bioorg. Med. Chem. Lett.
2007, 17. doi:10.1016/j.bmcl.2007.01.057.
sion and purification; Yuping Chen for the microsomal
stability data; and Antonio Oliveira-dos-Santos for
assistance with the biological assays.
References and notes
6. The kinase domain of human Lck (residues 225–501) with
a C-terminal His6 tag was expressed in insect cells and
purified by immobilized metal affinity, anion exchange,
and size exclusion chromatographies. The protein was
then phosphorylated by incubation with 5 mM Mg++Æ
ATP for 10 min at room temperature. Phosphorylated Lck
was further purified by anion exchange chromatography
and concentrated to 10 mg/mL. The coordinates for the
X-ray co-crystal structure of Lck and 1 have been
deposited in the PDB. The RCSB ID code is RCSB041056
and the PDB ID code is 2OF4.
7. For a discussion of CH–O hydrogen bonds in protein-
ligand complexes, see Pierce, A. C.; Sandretto, K. L.;
Bemis, G. W. Proteins: Struct. Funct. Genet. 2002, 49, 567.
8. Nunes, J. J.; Martin, M. W.; White, R.; McGowan, D.;
Bemis, J. E.; Kayser, F.; Fu, J.; Liu, J.; Jiao, X. Y. (Amgen
Inc.) Furanopyridine derivatives and methods of use. US
Pat. App. 2006046977 A1, 2006.
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12. For descriptions of all assays, see Ref. 3a.
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and 8 have been deposited in the PDB. The RCSB ID code
is RCSB041054 and the PDB ID code is 2OF2.
14. Previous work has shown that engaging this pocket is a
key element necessary for potency. See Ref. 3a.
15. The in vitro intrinsic clearances, CLint, of the test
compounds were determined by incubations with rat liver
microsomes purchased from BD Biosciences (San Jose,
CA). The 400 lL incubations contained 0.25 mg of
microsomal protein/mL, 1 mM NADPH, and 2 mM
MgCl2 in 50 mM potassium phosphate buffer, pH 7.4.
Test compounds were added to the pre-warmed (37 ꢁC)
incubation mixtures at the final concentration of 1 lM. At
0, 10, 20, 30, and 40 min following addition of test
compound, aliquots of the incubation mixture (35 lL)
were collected into an equal volume of acetonitrile +
internal standard (1 lM tolbutamide). The samples were
centrifuged at 3500g for 15 min and analyzed on a liquid
chromatography tandem mass spectrometry system con-
sisting of 2 Shimadzu LC-10AD HPLC pumps and a
DGU-14A degasser (Shimadzu, Columbia, MD), CTC
PAL autoinjector (Leap Technologies, Carrboro, NC) and
an API3000 LC-MSMS system. Chromatography was
conducted on a Sprite Armor C18 (20 · 2.1 mm, 10lm)
analytical column (Analytical Sales and Products, Pomp-
ton Plains, NJ) with a 0.5 lm PEEK guard filter, using the
following mobile phase gradient program: MPA = H20
with 0.1% formic acid; MPB = acetonitrile with 0.1%
formic acid; 0 min = 98% MPA, 2% MPB; 0.3 min = 98%
MPA, 2% MPB; 0.7 min = 5% MPA, 95% MPB;
1.3 min = 5% MPA, 95% MPB; 1.4 min = 98% MPA, 2%
MPB; 1.7 min = end of run; approximately 2 min between
sample injections. For each compound, peak areas at each
time point were converted to the natural log of the %
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remaining relative to the 0-min samples. The resulting
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slope of these values relative to time (k) was converted to
in vitro T1/2 where T1/2 = À0.693/k. CLint was calculated
using the following relationship: CLint = (0.693/T1/2)·(1/
0.25 mg/mL).
17. We believe the outlying value for the clogP of 15 can be
best rationalized by taking into account that these are
calculated and not measured values for logP.
16. For a discussion of the relationship between calculated
and physical properties with successful drug development,