Evolution of a New Class of VEGFR-2 Inhibitors from Scaffold Morphing and Redesign

Article abstract of DOI:10.1021/acsmedchemlett.5b00486

Anti-VEGF therapy is a clinically validated treatment for age-related macular degeneration (AMD). We have recently reported the discovery of oral VEGFR-2 inhibitors that are selectively distributed to the ocular tissues. Herein we report a further development of those compounds and in particular the validation of the hypothesis that aminoheterocycles such as aminoisoxazoles and aminopyrazoles could also function as effective "hinge" binding moieties leading to a new class of KDR (kinase insert domain containing receptor) inhibitors.

Full text of DOI:10.1021/acsmedchemlett.5b00486

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Letter
Evolution of a New Class of VEGFR-2 Inhibitors
from Scaffold Morphing and Redesign
Nello Mainolfi, Rajeshri Karki, Fang Liu, and Karen Anderson
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.5b00486 • Publication Date (Web): 02 Feb 2016
Downloaded from http://pubs.acs.org on February 4, 2016
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Evolution of a New Class of VEGFR-2 Inhibitors from Scaffold Morph-
ing and Redesign
Nello Mainolfi,*,‡,▲ Rajeshri Karki,*,‡ Fang Liu,§ Karen Anderson§
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‡Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA, 02139
USA.
§Ophthalmology, Novartis Institutes for Biomedical Research, 500 Technology Square, Cambridge, MA, 02139 USA.
KEYWORDS: Vascular Endothelial Growth Factor Receptor 2, VEGF, KDR, hinge binding, scaffold morphing, amino het-
erocycles.
ABSTRACT: Anti VEGF therapy is a clinically validated treatment for age related macular degeneration (AMD). We have recent-
ly reported the discovery of oral VEGFR-2 inhibitors that are selectively distributed to the ocular tissues. Herein we report a further
development of those compounds and in particular the validation of the hypothesis that aminoheterocycles such as aminoisoxazoles
and aminopyrazoles could also function as effective “hinge” binding moieties leading to a new class of KDR (Kinase Insert Domain
containing receptor) inhibitors.
series2 to phenyl ureas15 led us to hypothesize that compounds
INTRODUCTION
like 1 and 2 (Figure 1) bind in the DFG-out conformation of
The current approved therapies for the treatment of wet or
VEGFR-2, (confirmed subsequently by x-ray, unpublished
neovascular AMD are the anti-VEGF-A antibody ranibi-
data). Introduction of the polar amino-heterocycles (in place of
zumab, the anti-VEGF-A aptamer pegaptanib, and the anti-
the more classical meta-CF3 aniline) on our VEGFR-2 inhibi-
VEGF-A trap fusion protein aflibercept. Each of these wet-
tors provided a marked improvement in solubility, PK proper-
AMD treatments must be delivered by intravitreal injections
ties and also in VEGFR-2 potency.2 These findings, together
and sixty percent of patients do not experience a clinically
with the established role of heterocycles as “hinge binding”
significant gain of visual acuity (≥15 letters).1 In an attempt to
motifs in KDR literature,16, 17 inspired us to use this moiety to
provide an alternative wet-AMD treatment paradigm, we have
replace the pyrimidine “hinge” binding motif in our estab-
invested in the development of oral inhibitors of the receptor
lished series of inhibitors (1, Figure 1).
tyrosine kinase (RTK) VEGFR-2 (KDR, Flt-1).2, 3
The role of VEGF-A in the regulation of angiogenesis is
well established. Although new vessel growth and maturation
are highly complex processes requiring the sequential activa-
tion of a series of receptors by numerous ligands, VEGF-A
signaling often represents a critical rate-limiting step.4 VEGF-
A promotes growth of vascular endothelial cells and is also
known to induce vascular leakage.5 Ocular VEGF-A levels are
increased in neovascular diseases of the retina such as neovas-
cular AMD.6, 7
VEGF-A binds to two related receptor tyrosine kinases,
VEGFR-1 and VEGFR-2, both of which have an extracellular
domain consisting of seven immunoglobulin-like domains, a
single transmembrane region and a consensus tyrosine kinase
sequence that is interrupted by a kinase-insert domain.8 Upon
VEGF-A binding, VEGFR-2 undergoes dimerization and lig-
and-dependent tyrosine phosphorylation in intact cells, result-
ing in a mitogenic, chemotactic and survival signal.9 Crystal
structures of VEGFR-2 with and without inhibitors, exemplify
not only diversity in binding modes in DFG-in and DFG-out
forms of the kinase catalytic site,10 but also dependency on
juxtamembrane domain conformations.11 Several chemical
classes of VEGFR-2 inhibitors have been reported for oncolo-
gy indications and some of them have been investigated in wet
AMD.12-14 Structural similarity of our indole carboxamide
Figure 1. Hypothesis and design of new VEGFR-2 inhibitors
bearing a new “hinge” binding moiety starting from established
inhibitors.2, 3
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Scheme 1. Synthetic sequences to access compounds bearing new “hinge binding” moiety.a
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a Reagents and Conditions: (a) LDA (3.3 eq.), CH3CN (3 eq.), THF, -78 °C to rt; (b) hydroxylamine sulfate (1.1 eq.), NaOH (1.15 eq.),
EtOH, 80 °C, then HCl (1.5 eq.); (c) hydrazine (2 eq.), MeOH, 80 °C; (d) 1-isocyanato-3-(trifluoromethyl)benzene (1.5 eq.), THF, 0 °C for
10 and 12; phenyl (5-tert-butyl)isoxazol-3-yl)carbamate2 (3 eq.), DMF, 70 °C for 11 and 13; (e) 2,6-lutidine (2 eq.), benzyl carbono-
chloridate (1.5 eq.), DCM, 0 °C, then TFA/DCM, then 2,6-lutidine (4 eq.), 1-isocyanato-3-(trifluoromethyl)benzene (1.1 eq.), THF, 0 °C
for 14; 2,6-lutidine (2 eq.), benzyl carbonochloridate (1.5 eq.), DCM, 0 °C, then TFA/DCM, then 2,6-lutidine (4 eq.), phenyl (5-tert-
butyl)isoxazol-3-yl)carbamate2 (1.5 eq.), DMF, 70 °C for 15 and 19.
acetyl chloride for 23], DCM, rt then TFA/DCM, then 2,6-lutidine
(4 eq.), phenyl (5-tert-butyl)isoxazol-3-yl)carbamate2 (1.5 eq.),
DMF, 70 °C.
Scheme 2. Acylation of compounds 13 and 15 to expand SAR
in the “hinge” binding region.
Replacing the pyrimidine in 1 (Figure 1) with the aminohet-
erocycle of choice (pyrazole or isoxazole) was envisioned in
two ways: either directly attached to the core (3, in Figure 1)
or with a methylene linker (4 in Figure 1) to more closely
mimic the ether linker in inhibitor 1 (Figure 1). In addition, the
indole core was simplified to aniline given that previously
established SAR in that region allowed for such modification
to be tolerated.11 The synthesis of the newly designed com-
pounds outlined in Figure 1 started with the commercially
available Boc protected anilines 5 and 16 (Scheme 1). Trans-
formation of the ester to the nitriles 6 and 17 (precursors to the
aminoheterocycles formation) was accomplished using estab-
lished chemistry.2 Reaction of nitrile 6 with hydroxylamine
sulfate and sodium hydroxide in EtOH, followed by reaction
of the mixture with hydrochloric acid, furnished both the 3
amino- and 5 aminoisoxazoles 7 and 8 (respectively) as a
50/50 mixture with the loss of the protecting group.18, 19 Reac-
tion of nitriles 6 and 17 with hydrazine in MeOH gave the
expected aminopyrazoles 9 and 18.20 In the case of aminoisox-
azoles 7 and 8 simple urea formation of the anilines with ei-
ther isocyanate or phenyl carbamates efficiently produced the
wanted ureas 10-13 (see supporting information for separation
conditions to isolate the single isomers). In the case of the
aminopyrazoles 9 and 18, a temporary protection of the ami-
nopyrazole moiety (as a benzylcarbamate) was needed in order
a Reagents and Conditions: (f) pyridine (2 eq.), cyclopropanecar-
bonyl chloride (1.5 eq.), THF, 0 °C; (g) 2,6-lutidine (2 eq.), ben-
zyl carbonochloridate (1.5 eq.), DCM, 0 °C, then 2,6-lutidine (2
eq.), cyclopropanecarbonyl (for 21) [pyvaloyl chloride for 22,
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to efficiently couple the aniline (after Boc deprotection) with Table 1. In vitro VEGFR-2 inhibitory potency for compounds
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the isocyanates or phenyl carbamates to get the desired ureas
14, 15 and 19 (Scheme 1). Acylation of the free aminoisoxa-
zole 13 with cyclopropanecarbonyl chloride and pyridine easi-
ly furnished the wanted inhibitor 20 (Scheme 2). For aminopy-
razole containing compounds, acylation of the NH2, required a
protection of the more reactive ring nitrogen (as a benzy-
lacarbamate), followed by acylation of the amine with electro-
philes. This was followed by deprotection of the aniline to
enable urea formation with the carbamate. In vitro inhibition
of VEGFR-2 receptor tyrosine kinase was assessed with two
primary assays; a KDR receptor tyrosine kinase biochemical
assay and a cellular assay with BaF3-Tel-KDR cells that are
engineered to constitutively require VEGFR-2 kinase domain
activity for survival and proliferation.
produced via Scheme 1.
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When we decided to investigate the ability of the aminohet-
erocyles in question to be efficient “hinge” binding moieties,
we decided to include the more historically validated phenyl
ureas together with the aminoheterocycle based ureas. The
first set of compounds tested were all possible combinations of
aminoisoxazole isomers, aminopyrazoles and ureas (Table 1).
Both enzymatic and cellular data showed that the 3-
aminoisoxazole (compounds 10 and 11, Table 1) was not a
suitable group for hinge interaction. The 5-aminoisoxazole
compounds 12 and 13, however, showed some interesting
activity especially in combination with the heterocycle based
urea 13 (1.9 and 2.4 μM in biochemical and cellular assay
respectively). Of note, this type of urea SAR was also seen in
the pyrimidine based series of VEGFR-2 inhibitors).2 The
aminopyrazoles 14 and 15 also showed a promising potency
profile pointing to the key role of the 1-3 relationship between
the amino group and the ring nitrogen (not present in com-
pounds 10 and 11), and a possible contribution of the second
ring nitrogen at the 2 position. Aminopyrazole 19 was synthe-
sized to explore if addition of a flexible linker would more
closely replicate the spatial orientation of the progenitor series
(compound 1, Figure 1). The disappointing biochemical po-
tency of 19 (6.6 μM) directed further efforts to the improve-
ment of inhibitors 13 and 15 especially around the “hinge”
binding region. Cyclopropancarboxamide analogues of 13 and
15 helped in differentiating and in the selection of the better
hinge binding motif (Table 2). Compound 21 with a pyrazole
group for hinge binding was 400-fold more active than the
isoxazole 20. This also demonstrated for the first time acylated
aminopyrazole 21 as a potent VEGFR-2 inhibitor with excel-
lent biochemical and cellular potency (11 and 43 nM respec-
tively) and in doing so validating the initial hypothesis that
aminoheterocycles could function as pyrimidine replacements
in this series of KDR inhibitors. Pyvaloyl (compound 22) and
acetyl (compound 23) analogs of 21 supported the initial find-
ing of pyrazolyl amide as efficient hinge binders, leading to
potent inhibition of VEGFR-2.
aValues are mean of at least two experiments (IC50 µM).
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Table 2. Impact of the amino heterocycles on VEGFR-2 in-
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hibitory potency.
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Figure 2. Modeled binding mode of 21 (blue) in the ATP-binding
site of VEGF-R2 (white). Hydrogen bonding interactions are
shown in black dotted lines.
aValues are mean of at least two experiments (IC50 µM).
ASSOCIATED CONTENT
Supporting Information. Experimental procedures for all com-
pounds in Table 1 and Table 2. This material is available free of
charge via the Internet at http://pubs.acs.org.
Molecular modeling21 of compounds 20 and 21 in the ATP-
site of VEGFR-2 rationalized the potency differences seen for
these inhibitors. As shown in Figure 2, aminopyrazole of in-
hibitor 21 makes H-bonding interactions with Glu917, Phe918
and Cys919 in the hinge while the urea makes H-bonding in-
teraction with Asp1046 and bi-dentate H-bonding with
Glu885. The ter-butyl group is located in a hydrophobic pock-
et surrounded by residues: Ile892, Val898, Leu1019,
Met1016, His1026 and Ile1044. Inhibitor 20 can elicit similar
binding mode, with the major difference observed in its inter-
actions in the hinge region. While the donor –NH of pyrazole
in 21 can make an additional H-bonding with Glu97 backbone
carbonyl, in case of inhibitor 20 the acceptor oxygen in isoxa-
zole will be electrostatically repulsive thereby causing loss in
binding affinity and potency.
AUTHOR INFORMATION
Corresponding Author
*Nello Mainolfi: nello@razetx.com and Rajeshri Karki: raje-
shri.karki@novartis.com.
Present Address
▲N.M.: Raze Therapeutics, 400 Technology Square, Cambridge,
MA 02139.
ACKNOWLEDGMENT
We have thus validated the hypothesis that simple aminohet-
erocycles can replace the pyrimidine in a well-established
series of VEGFR-2 inhibitors2 and function as effective
“hinge” binding moieties. It was also shown how aminopyra-
zoles are more efficient than aminoisoxazoles in binding in the
ATP binding site of KDR substantiating empirical findings
with molecular modeling experiments. The reported findings
could have a substantial impact on the chemical diversity,
physicochemical properties and in vivo distribution profile of
new series of VEFGR-2 inhibitors and hopefully offer further
avenues towards new and less invasive therapies for patients
suffering from AMD.
The authors acknowledge the contribution of the Analytical Sci-
ences group at the Novartis Institute for Biomedical Research for
support in generating the analytical details for the compounds
described herein.
ABBREVIATIONS
AMD, Age related Macular Degeneration; VEGF, Vascular Endo-
thelial Growth factor; Flt-1, FMS-like tyrosine kinase 1; VEGFR-
2, Vascular Endothelial Growth factor Receptor 2.
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