Discovery of a novel class of imidazo[1,2-a ]pyridines with potent PDGFR activity and oral bioavailability

Article abstract of DOI:10.1021/ml4003953

The in silico construction of a PDGFRβ kinase homology model and ensuing medicinal chemistry guided by molecular modeling, led to the identification of potent, small molecule inhibitors of PDGFR. Subsequent exploration of structure-activity relationships

Full text of DOI:10.1021/ml4003953

Letter
pubs.acs.org/acsmedchemlett
Discovery of a Novel Class of Imidazo[1,2‑a]Pyridines with Potent
PDGFR Activity and Oral Bioavailability
Erik J. Hicken,* Fred P. Marmsater, Mark C. Munson, Stephen T. Schlachter, John E. Robinson,
Shelley Allen, Laurence E. Burgess, Robert Kirk DeLisle, James P. Rizzi, George T. Topalov, Qian Zhao,
Julie M. Hicks, Nicholas C. Kallan, Eugene Tarlton, Andrew Allen, Michele Callejo, April Cox,
Sumeet Rana, Nathalie Klopfenstein, Richard Woessner, and Joseph P. Lyssikatos
Department of Drug Discovery, Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States
S
* Supporting Information
ABSTRACT: The in silico construction of a PDGFRβ kinase homology
model and ensuing medicinal chemistry guided by molecular modeling, led
to the identification of potent, small molecule inhibitors of PDGFR.
Subsequent exploration of structure−activity relationships (SAR) led to
the incorporation of a constrained secondary amine to enhance selectivity.
Further refinements led to the integration of a fluorine substituted
piperidine, which resulted in significant reduction of P-glycoprotein (Pgp)
mediated efflux and improved bioavailability. Compound 28 displayed oral exposure in rodents and had a pronounced effect in a
pharmacokinetic−pharmacodynamic (PKPD) assay.
KEYWORDS: Platelet-derived growth factor, fluoro-piperidine, fluorine, Pgp
however, include crystal structures of other members of the
PDGFR and VEGFR families, namely, cFMS, cKIT, FLT3,
KDR (VEGFR2), and FLT1 (VEGFR1). Many of these crystal
structures also contain small molecule inhibitors cocrystallized
in the ATP binding site. From this information, we can discern
that there are minor protein sequence variations within the
ATP binding pockets of these kinase families.13 Our approach
was to take advantage of the differences in sequence as well as
the observed subtle differences in ATP-binding site shapes in
order to impart the desired PDGFR selectivity to our inhibitors.
By using a published cFMS crystal structure and the known
amino acid sequence of PDGFRβ, we constructed a model of
PDGFRβ in silico. This model was then used to design novel
small molecule antagonists containing an imidazopyridine to
interact with the hinge region of PDGFRβ (Figure 1). Docking
studies predicted that the addition of an amine would provide
an interaction with the side chain of either an aspartic acid (i.e.,
ASP-111) or an asparagine (i.e., ASN-253) in the outer floor.
The backbone carbonyl of arginine-252 was predicted to
provide another polar interaction for a small molecule inhibitor.
These interactions were predicted to provide compounds with
good PDGFRβ potency, as well as potentially provide
selectivity over members of the VEGFR family based on the
expected variation in protein structure between kinases.13 This
effort culminated in the design of a novel series of
imidazopyridines.14
latelet-derived growth factor receptor (PDGFR) is an
1,2
Pattractive target for treating malignant disease.
Con-
stitutive activation of PDGFR resulting from point mutations,
chromosomal translocations, and autocrine loops have been
described in gastrointestinal stromal tumors (GIST) and
gliomas.3 PDGFR also plays an important role in the
remodeling and maintenance of blood vessels (neovasculature)
through its regulation of pericytes, suggesting that inhibitors of
PDGFR could have broad utility against a spectrum of human
cancers as antiangiogenic agents.4,5 In addition, PDGFR has
been shown to be a potent mitogen for myofibroblast
formation, a signature event in the progression of fibrosis.6
The availability of a potent, selective, orally bioavailable
PDGFR inhibitor would help define the role of the kinase in
tumor growth, angiongenesis and fibrosis.
Although a few approved kinase inhibitors possess PDGFR
inhibitory activity, their primary activity is targeted toward Abl
or KDR, and dose escalation is often limited by attendant
toxicities (i.e., Imatinib, Dasatinib, Sorafenib, Sunitinib, etc.).
Prior to our investigation, two selective small-molecule
inhibitors of PDGFR had been described in the literature.7−9
We set out to discover and develop a novel, orally bioavailable,
selective, and potent PDGFR antagonist using structure-based
drug design strategies.
PDGFR belongs to the receptor tyrosine kinase class 3
(RTKIII), which comprises members of the PDGFR family,
including PDGFRα, PDGFRβ, cKIT, cFMS, and FLT3. A
highly related group of kinases include the VEGFR family,
FLT1, FLT4, and KDR.10−12 Although the sequence of
PDGFR is known, there are no reported PDGFR crystal
structures. The Protein Data Bank (www.pdb.org) does,
Received: October 3, 2013
Accepted: November 12, 2013
© XXXX American Chemical Society
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chloride and catalytic DMF in DCE at 85 °C provided the
coupling partner 8 (Scheme 1).
Scheme 1. Synthesis of Key Coupling Partners
Figure 1. View of 1 docked into the ATP binding site of a PDGFRβ
kinase homology model. Location of PDGFR residues are labeled for
clarity.
With the key partners in hand we were able to couple 5 and
8 via a Heck-type reaction using a mixed catalyst system of
Pd(PPh3)4 and Pd(OAc)2 in dioxane and water.17,18 The
residual benzyl protecting group was then removed using
Pd(OH)2 on carbon in the presence of ammonium formate to
afford 9 (Scheme 2). This useful, advanced intermediate was
An early example of this series (1, see Figures 1 and 2)
demonstrated an IC50 of 18 nM in our PDGFRβ cell assay.15
A
Scheme 2. Coupling and Alkylation Endgame of Synthesis
Figure 2. Structure and activity profile for compound 1.
molecular modeling view of compound 1 bound to the active
site of PDGFRβ is shown in Figure 1, with the key residues
highlighted. Although compound 1 was a potent PDGFRβ
antagonist, selectivity over other members of the PDGFRβ and
VEGFR families was limited (FLT3, cFMS, and KDR = <10×).
We hypothesized that this poor selectivity was due to the high
degree of conformational flexibility of the propyl-amine,
allowing for a variety of polar interactions to be established
within familial kinases. Consequently, we designed constrained
analogues of 1 that could procure improved kinase selectivity
(>10×) based on PDGFRβ specific residues.
With the identification of 1, our medicinal chemistry efforts
focused on the development of a synthetic route that would
allow for late stage diversification of the amine headgroup. This
effort resulted in a highly convergent synthesis that began with
commercially available nitropyridine 2, which was treated with
2-methoxyethanol in the presence of a strong base to provide
chloropyridine 3, which was used directly in the next step
without purification. Compound 4 was obtained by the
treatment of 3 with LiHMDS in the presence of Pd and X-
Phos, followed by exposure to aqueous acid.16 Cyclization of 4
was performed with aqueous chloroacetaldehyde at 50 °C to
afford the key imidazopyridine 5. The quinoline core was
obtained by starting with commercially available quinoline diol
6, which was exposed to benzyl bromide in the presence of
K2CO3 to provide 7. Treatment of quinolinol 7 with oxalyl
conveniently alkylated with mesylates such as 10 using Cs2CO3
in DMA to afford final products having an amine headgroup,
after TFA-mediated removal of the BOC protecting group.
This synthetic sequence was highly convergent and allowed for
robust generation of diverse structure−activity relationships
(SAR) around the amine headgroup, providing compounds
such as 11.
With the development of a robust synthesis for the formation
of 9, we began our refinement of 1 by searching for a
constrained amine headgroup that would provide the desired
selectivity (>10×) over members of the PDGFRβ and VEGFR
families (Table 1). In general, the spatial orientation of the
amine played an important role toward PDGFRβ potency and
selectivity. With the aid of our PDGFRβ homology model, we
found that it was possible to design an amine headgroup that
B
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a
Table 1. In Vitro Potency of Compounds 11−26
a
b
Key: ‡, denotes racemic compound, relative stereochemistry is as depicted; *, denotes single enantiomer. ND = not determined. All compounds
c
with PDGFR IC50 values of <100 nM were run at least in duplicate. All compounds were run in this assay at least in duplicate; value shown is an
average of the assay results.
a
Table 2. In Vitro Profile of Compounds 11 and 27−29
a
Key: *, compound cis-27 had an IC50 of 5880 nM on CYP 2D6; ‡, the absolute stereochemistry of 28 and 29 are arbitrarily assigned.
C
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would provide good PDGFRβ potency and improved kinase
selectivity when compared to 1. Surprisingly, some amine
headgroups were found to provide analogues having excellent
selectivity over cFMS and cKIT (>100×), despite the same
amino acid residues being located at the outer floor of the
binding pocket. This is potentially due to the specific location
of the polar residues in the outer floor of PDGFRβ, such as
ASP-111 and ARG-252, and our use of a rigid amine
headgroup. In addition, we found that >10× selectivity15 over
KDR could be obtained with a variety of amine headgroups
(14, 15, 18, 21, and 22), with the observed increase in
PDGFRβ potency likely due to optimized binding with the
polar residues in the outer floor. Some flexibility in the distance
between the quinolone and amine NH was tolerated, with 2 to
3 carbon atoms between the quinoline oxygen and amine
appearing optimal in cyclized amines (i.e., 11 and 15) but an
optimal length was observed (11 vs 19). Secondary cyclic
amines were preferred over primary acyclic amines (1 and 26 vs
11). It was found that pyrrolidine headgroups were well
tolerated (21 and 22) except when the carbon adjacent to the
amine was substituted (23 and 24). Alkylation of the amine
(12) decreased PDGFRβ potency while leaving KDR potency
unchanged. In addition, it was determined that the absolute
configuration of a chiral amine can play a significant role in
potency (15 vs 16).
After substantial effort we determined that compound 11 had
achieved the target properties of potency and selectivity (>10×
over KDR and >100× over cFMS, see Table 1) providing the
desired improvements over 1.15 Although we had discovered
alternative compounds that were more potent than 11, the
overall in vitro properties of 11 were superior. This
determination was based on a combination of properties,
including stability (i.e., 14 had >70% microsomal clearance in
rodents and cyno), low cell shift in the presence of human
plasma (i.e., PDGFRβ cellular assay run in the presence of 50%
human plasma; 21 = 29 nM, 22 = >1000 nM), and selectivity
over members of the RTKIII family.15 The profile of 11 is
summarized in Table 2. Our lead compound 11 had excellent
selectivity over cKIT and cFMS (>100×), was clean on all
tested subtypes of cytochrome p450 (>10 μM), and was potent
in the cellular assay in the presence of 50% human plasma (25
nM). Subsequently, 11 was progressed to rat PK, which
revealed that compound 11 suffered from poor oral exposure
(16% F, dosed as a 20% Solutol aqueous solution, see Table 3).
efflux. By attenuating the pKa of the piperdine amine, we hoped
to positively influence passive permeability19−22 and reduce Pgp
mediated efflux.23−25 Attempts had been made earlier to reduce
the pKa of 11 by employing a morpholine headgroup (20),
installing an ether or hydroxyl on the ring (17, 18, and 22),
moving the amine closer to the ether linkage (15 and 26) or
installing an ester adjacent to the amine (23 and 24).
Unfortunately, these attempts either decreased PDGFRβ
potency or led to high predicted microsomal clearance.
Our focus then turned to the utility of fluorine. It is well
precedented that introduction of a highly polarized and strong
C−F bond (105 kcal/mol) can reduce the basicity of proximal
amines.26,27 In addition, installation of fluorine not only creates
a strong C−F bond but also leads to increases in the strength of
adjacent C−O and C−C bonds.28,29 Therefore, the addition of
fluorine on the piperidine ring had the potential to not only
attenuate the amine basicity but also enhance metabolic
stability.
Accordingly, we installed a single fluorine atom on the
piperidine ring (Table 2), arriving at two racemic but
diastereomerically pure compounds, cis-27 and trans-27. For
cyclic alkyl amines, the decrease of pKa from an axial fluorine
substituent can be considerably smaller than that seen for an
equatorial fluorine.23−25 Therefore, the relative orientation of
the fluorine substituent can have an effect on the pKa of the
piperidine amine. On the basis of our experimental measure-
ment, we found that the fluorine atom had attenuated the pKa
nearly two units, from 9.3 for compound 11 to 7.4 for trans-27.
Although we had anticipated a difference in the pKa of cis-27
and trans-27, they were essentially the same.
We anticipated that the observed decrease in pKa of the
piperidine amine would be sufficient to increase the passive
permeability of 11 while decreasing Pgp mediated efflux and
lead to improved bioavailability.19−25 During our in vitro
profiling of these compounds, we were surprised to find that
installation of a fluorine atom on the piperidine ring had caused
a reduction in the apparent permeability of both cis- and trans-
27 when compared to compound 11 (albeit with attenuated
apical recoveries of 30% for 27). This result is in contrast to our
previous experience, as well as literature precedents that suggest
a more neutral species (i.e., decreasing the pKa of a basic
amine) will improve membrane permeability.19−25 Although
the apparent permeability of cis-27 and trans-27 had been
reduced, Pgp mediated efflux was significantly decreased, as
seen in the MDR1 cell line assay, when compared to 11.
Both cis- and trans-27 were then progressed into rat
pharmacokinetic studies. The results demonstrate that the
installation of fluorine clearly reduced the IV clearance, from 33
(11) to 24 mL/min/kg (trans-27). Despite the improvement in
IV clearance, cis-27 was unexpectedly indistinguishable from 11
in rat PK (Table 3). Conversely, trans-27 had significantly
better in vivo exposure (2−3× improved AUC, Cmax, and % F)
than cis-27 and 11. We were gratified to find that the
installation of a single fluorine atom had not only aided in
maintaining the desired potency and selectivity but provided a
significant improvement in oral bioavailability.
Table 3. Male Rat PK Profile of Compounds 11, 27, and 28
male rat PK
1 mg/kg IV
11
33
cis-27 trans‑27
28
20
CL (mL/min/kg)
ER
28
24
48
41
34
29
10 mg/kg PO
AUC (μg)(hr)/mL
Cmax (μg/mL)
% F
0.80
0.07
16
0.73
0.07
13
2.1
0.12
30
2.3
0.16
28
These data, in combination with moderate IV clearance and
excellent solubility (>1000 μg/mL) suggested that the poor
oral exposure was not solely due to in vivo instability.
Compound 11 was analyzed in a MDR1 cell line assay, and
although attenuated apical recoveries were noted (50%
recovery), it displayed high passive permeability along with
efflux transport by P-glycoprotein (Pgp) (Pe ratio = 5.7).
The measured pKa of 11 was found to be 9.3, which
facilitated good solubility but potentially played a role in Pgp
With the identification of trans-27, we separated and profiled
the enantiomers 28 and 29, to determine if they would
differentiate (the absolute stereochemistry shown for 28 and 29
are arbitrarily assigned). These two compounds were nearly
identical in all assays with the exception of the KDR enzyme
assay, in which 28 was 53 nM on KDR and 17× selective for
PDGFRβ, versus the less selective 29, which was 16 nM on
D
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KDR and only 5× selective for PDGFRβ.15 When fluoro
piperdine 28 was evaluated in vitro, it was found to maintain
the desirable properties of 11 while improving upon 11 by
lowering Pgp efflux. Oral exposure of 28 in rat was improved
when compared to 11 with a concomitant decrease in IV
clearance (see Table 3).
Compound 28 was also evaluated in a pharmacokinetic−
pharmacodynamic (PKPD) assay, which we employed as a
surrogate for the efficacy of our PDGFR inhibitors (Figure 3).
2). The resulting lack of exposure in monkeys prevented
tolerability assessment in second species and prohibited
additional studies. Within this series we have established robust
IV/IV correlation in both rat and monkeys. As these analogues
consistently display high first pass clearance in second species,
complicating preclinical toxicology assessment, we continued
our medicinal chemistry efforts toward the development of a
compound with improved oral exposure and decreased
clearance in second species. These efforts will be addressed in
a subsequent manuscript.
ASSOCIATED CONTENT
* Supporting Information
■
S
Protocol of the PDGFR cellular assay and pharmacokinetic/
pharmacodynamic assay. Experimental procedures for the
synthesis and chacterization of 3−11, 27, and 28. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*(E.J.H.) Tel: 303-386-1282. E-mail: erik.hicken@
arraybiopharma.com.
■
Notes
Figure 3. PKPD study of compound 28 as a single oral dose. Multiple
time points and doses were evaluated. The ratio of pPDGFR/tERK
was measured and compared to control.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We would like to thank Philip Anderson and Ben Colson for
obtaining HRMS and pKa data, respectively.
■
The PKPD experiment was performed in female nude mice
bearing subcutaneous C6 tumor xenografts. pPDGFR levels
were determined and the values normalized to TotalERK by
Western Blot. Compound 28 was evaluated at three different
time points and at three doses. Following oral administration of
28 as a single dose, a PD response was observed in a dose-
dependent manner. The effect of 28 was maximized at the 6 h
time point with pPDGFR levels returning to those of the
control after 12 h. On the basis of this data, the EC50 of 28 was
determined to be a total drug concentration of 65 ng/mL.
Compound 28 was determined to be an excellent compound
for the investigation of PDGFRβ inhibition in rodents and was
well tolerated on chronic PO dosing in rats at doses of up to 50
mg/kg BID for two weeks. However, it suffered from high
clearance in cynomolgus monkeys (see Table 4), which was
predicted by the in vitro microsome stability assay of 28 (Table
ABBREVIATIONS
■
AUC, total area under the plasma drug concentration−time
curve; DBA(dba), dibenzylideneacetone; DCE, 1,1-dichloro-
ethane; ER, extraction ratio; HMDS, 1,1,1,3,3,3-hexamethyldi-
silazane; MDR1, multidrug resistance gene; PDGFR, platlet-
derived growth factor receptor; Pgp, P-glycoprotein; PK,
pharmacokinetic; pKa, logarithmic acid dissociation constant;
PKPD, pharmacokinetic−pharmacodynamic; SAR, structure−
activity relationship; TFA, trifluoroacetic acid; X-Phos, 2-
dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl
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