Discovery of a highly potent, orally active mitosis/angiogenesis inhibitor R1530 for the treatment of solid tumors

Article abstract of DOI:10.1021/ml300351e

A new series of 7,8-disubstituted pyrazolobenzodiazepines based on the lead compound 1 have been synthesized and evaluated for their effects on mitosis and angiogenesis. Described herein is the design, synthesis, SAR, and antitumor activity of these compo

Full text of DOI:10.1021/ml300351e

Letter
pubs.acs.org/acsmedchemlett
Discovery of a Highly Potent, Orally Active Mitosis/Angiogenesis
Inhibitor R1530 for the Treatment of Solid Tumors
Jin-Jun Liu,*,† Brian Higgins,‡ Grace Ju,‡ Kenneth Kolinsky,‡ Kin-Chun Luk,*,† Kathryn Packman,‡
Giacomo Pizzolato,† Yi Ren,§ Kshitij Thakkar,† Christian Tovar,‡ Zhuming Zhang,†
and Peter M. Wovkulich*,†
†Discovery Chemistry, ‡Discovery Oncology, and §Chemical Synthesis, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, New
Jersey 07110, United States
S
* Supporting Information
ABSTRACT: A new series of 7,8-disubstituted pyrazolobenzodiazepines based on the lead
compound 1 have been synthesized and evaluated for their effects on mitosis and angiogenesis.
Described herein is the design, synthesis, SAR, and antitumor activity of these compounds leading
to the identification of R1530, which was selected for clinical evaluation.
KEYWORDS: pyrazolobenzodiazepines, mitosis/angiogenesis inhibitor, antitumor effect, VGFr-2, FGFr and PDGFr-β
eventually identified compound 2 (R1530) as a highly potent,
orally bioavailable, dual-acting mitosis/angiogenesis inhibitor
for the treatment of solid tumors. These biological attributes of
R1530 have been explicitly discussed in prior reports.25,26 We
describe herein the synthesis and biological evaluation of
R1530.
Our early preparations of R1530 were part of an effort
designed to probe the structure−activity relationship of
disubstitution at the 7- and 8-position (Figure 1). For maximal
ngiogenesis, the growth of new blood vessels, is an
Aessential component in the progression and metastasis of
tumors. Therapeutic regimens in oncology frequently employ
combinations of agents in an attempt to maximize efficacy.
Targeting angiogenesis pathways1−9 and mitotic processes are
among the many combinations currently undergoing clinical
study and, from recent reports, appear to offer some promise of
improved clinical response.10−13 We were interested in further
exploring our new pyrazolobenzodiazepine kinase inhibitor
template in this context.
We have recently described the discovery of pyrazolobenzo-
diazepines14 as ATP competitive kinase inhibitors and their
optimization to compound 1.15 Compound 1 showed potent
inhibitory activities against kinases, such as cyclin-dependent
kinases (CDKs) 2 and 4, and angiogenesis-related growth
factor receptor tyrosine kinases, such as kinase insert domain
receptor (KDR), fibroblast growth factor receptor (FGFr),
platelet-derived growth factor receptor (PDGFr), and epi-
dermal growth factor receptor (EGFr). It also exhibited potent
in vitro antiproliferative activity in a wide range of human
tumor cell lines derived from different tissue types. While the
antiangiogenic activities appear to be separate from the
antiproliferative activities, the precise target for the antiprolifer-
ative activity remains elusive. The noteworthy antiangiogenic
activity and antitumor activity of compound 1 in mouse
models9,16 proved a compelling argument for further
investigation. However, an unattractive ADMET profile
rendered the compound less interesting for human evaluation.
We then directed our attention to modifications at the 7- and 8-
positions on the fused benzene ring in an attempt to improve
on the kinase inhibitory activities and ADME properties and
Figure 1.
adaptability with respect to scalability and convergence in the
early stages, we developed two general routes. Commercially
available disubstituted anilines 3 were reacted with 2-
chlorobenzonitrile 4 via the Sugasawa reaction17,18 in the
19
presence of BCl3 and GaCl3 in toluene to give the
intermediate imines 5, which formed the corresponding
benzodiazepines 6 by treatment with MeOCOCH2NH3Cl in
a mixture of AcOH and iPrOH. 7-Alkoxy-8-fluoro imines 5
derivatives were obtained by treatment of the corresponding
difluoro imines 5 (R1, R2 = F) with the appropriate alcohols (R2
Received: November 8, 2012
Accepted: January 15, 2013
© XXXX American Chemical Society
A
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ACS Medicinal Chemistry Letters
Letter
= OR) and NaOR. Benzodiazepines 6 were then converted to
the desired 7,8-disubstituted pyrazolobenzodiazepine 2 in three
steps as described previously (Scheme 1).15 Alternatively,
way to access a variety of substituent groups on the benzene
ring, while the linear synthesis gives a better overall yield for a
specific analogue.22
By using these methods, a broad range of 7,8-disubstituted
pyrazolobenzodiazepine analogues were evaluated (data not
shown), of which R1530 (compound 2) emerged based on its
biological activities and pharmacokinetics (PK) properties
Of particular interest, R1530 as compared to the
monosubstituted compound 1 showed stronger inhibitory
activities against angiogenesis-related receptor tyrosine kinases
(KDR, FGFr) and weaker activities against CDK2 and -4
(Table 1), indicating the feasibility of improving potency and
selectivity for the angiogenesis-related kinases.
a
Scheme 1. Synthesis of Compound 2
Table 1. Kinase Inhibition of Selected Mono- and 7,8-
a
Disubstituted Pyrazolobenzodiazepines (IC50 μM)
compd
KDR
FGFr1
CDK2
CDK4
a
1
2
0.034
0.010
0.050
0.028
0.088
1.330
0.303
>10
Reagents and conditions: (a) BCl3/GaCl3/toluene, reflux. (b)
NaOR/ROH, reflux. (c) MeOCOCH2NH3Cl/AcOH/iPrOH, reflux.
(d) MeCHO. (e) Hydrazine. (f) Air oxidation, DMSO, 150 °C.
Values are the means of duplicate experiments.16
a
compounds 2 could be prepared in a more convergent manner
as outlined in Scheme 2. A microwave-promoted coupling
R1530 was profiled first in an in-house panel of 30 kinases. In
addition to confirming the previously mentioned kinases, this
first round of profiling identified two kinases associated with
G2/M phase activities, Aurora A (58 nM) and checkpoint
kinase 2 (Chk2) (24 nM). The compound was then evaluated
in an Ambit panel of 178 kinases, with Kd values determined for
those kinases showing >85% signal at 1 μM23,24 (Supple-
mentary Table 1 in the Supporting Information).
a
Scheme 2. Convergent Synthesis of Compound 2
The in vitro antiproliferative effects of R1530 were further
evaluated by the tetrazolium dye assay (MTT) in human tumor
cell lines originating from various human tumor tissues
including breast, colon, lung, prostate, melanoma, and oral
epidermoid (Supplementary Table 2 in the Supporting
Information). R1530 exhibited potent in vitro antiproliferative
activity in all of the tumor cell lines tested (IC50 = 0.2−3.4
μM). Because of its ability to inhibit the kinase activities of
vascular endothelial growth factor receptor 2 (VGFr2), FGFr1,
and PDGFr-β, R1530 was further characterized for its effects on
VEGF and bFGF-induced proliferation of human umbilical vein
endothelial cells (HUVEC) and PDGF driven fibroblast
proliferation. R1530 showed strong inhibition of VEGF and
bFGF induced HUVEC proliferation (IC50 = 49 and 118 nM);
however, activity in the PDGF driven assay was less potent
(IC50 = 688 nM).
a
Reagents and conditions: (a) BCl3/GaCl3/toluene, reflux. (b) MnO2.
(c) MeOH/NAOMe, reflux. (d) TEA, 80 °C, 3 h. (e) CuCl2/NaNO2/
HCl (49%, two steps). (f) NaOH. (g) ClCOOEt/TEA/NaN3. (h)
HCl, 110 °C, 2 h (50%, three steps). (i) TsOH/iPrOH/microwave,
170 °C, 15 min. (j) DIBAH/THF/(dppp)NiCl2.
R1530 disrupts cells in mitosis, an effect less consistent with
the inhibition of CDK2 and CDK4 and more in line with the
interference of tubulin polymerization and inhibition of
checkpoint kinases.11 The working hypothesis of R1530
antitumor effect is unique and is classified as being the product
of mitotic slippage, subsequently followed by induction of
endoreduplication and the generation of polyploidy. The
resultant effect of R1530 on cells is apoptosis (mitotic
catastrophe) or senescence (Figure 2). These direct antitumor
cell effects in combination with the antiangiogenic activity
ultimately translate into potent in vivo efficacy. Normal
proliferating cells were resistant to R1530 induced polyploidy.25
R1530 showed acceptable PK properties in multispecies. The
single-dose PK of R1530 were generally similar among the
mouse, rat, and monkey: following intravenous injection, the
volume of distribution at steady state (Vdss) was generally high
(1.59−3.22 L/kg), the total plasma clearance (CL) was
reaction between disubstituted benzophenone 9 and 1-allyl-5-
chloro-3-methyl-1H-pyrazol-4-ylamine 13 followed by removal
of the allyl group using the general method described in the
literature20 provided 2 in moderate yields. The disubstituted
benzophenones 8 were made from commercially available
disubstituted anilines 3 by reacting with 2-chlorobenzaldehyde
7 using BCl3 and GaCl3 as catalysts, followed by oxidation with
MnO2. The 8-alkoxy benzophenones 9 were conveniently
derived from the difluoro-substituted benzophenone 8 (R1 = R2
= F) by the regioselective replacement reaction with alcohols in
the presence of base. The 1-allyl-5-chloro-3-methyl-1H-pyrazol-
4-ylamine 13 was prepared by condensation of 2-cyano-3-
ethoxy-but-2-enoic acid ethyl ester 10 and allyl-hydrazine 11
followed by diazotization, chloride formation, and subsequent
Curtius reaction.21 The convergent route represents a quick
B
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ACS Medicinal Chemistry Letters
Letter
Figure 2. Working hypothesis of R1530 antitumor effect.
moderate to high (469−528 mL/kg/h), while the terminal
elimination half-life (T1/2) was between 3 and 5 h (Table 2).
Following single-dose oral administration, R1530 was generally
well absorbed, with high oral bioavailability in rodents and
moderate bioavailability in monkeys (Table 3).
Table 2. Single iv Dose PK of R1530
species
mouse
rat
5
monkey
dose (mg/kg)
CL (mL/kg/h)
Vss (L/kg)
5
528
3.12
4.32
1
469
1.59
3.83
527
3.22
4.70
half-life (h)
Figure 3. Efficacy studies of R1530 in mice utilizing MDA-MB-435
human tumor xenograft model.
Table 3. Single Oral Dose PK of R1530
species
mouse
rat
50
monkey
Figure 1 in the Supporting Information) with the third (22rv1,
Supplementary Figure 2 in the Supporting Information)
yielding 98% tumor growth inhibition (TGI). The 1.56 mg/
kg dose was not efficacious in either the HCT116
(Supplementary Figure 3 in the Supporting Information) or
the A549 model (Supplementary Figure 4 in the Supporting
Information). No signs of toxicity were noted in any of the dose
groups as assessed by measuring changes in body weight and
gross observation of individual animals (data not shown).
There was a biologically significant increase in survival (≥25%)
in all groups dosed with 25 or 50 mg/kg of R1530 regardless of
the xenograft models tested.26
dose (mg/kg)
Tmax (h)
25
2
10
4−8
406
4−8
5360
Cmax (ng/mL)
AUC0−24h (ng h/mL)
F (%)
5070
46700
96.9
86300
4820
22.1
88.7
Efficacy studies of R1530 were conducted in mice utilizing
various human tumor xenograft models.26 Animals were dosed
orally, once a day (qd) at 1.56, 25, or 50 mg/kg. R1530
produced significant tumor growth inhibition in all models
tested, with regression observed in all models tested at a 50
mg/kg dose. In the three models where 1/2 MTD (25 mg/kg)
of R1530 was tested, regressions were observed in two out of
three models (MDA-MB-435, Figure 3; LoVo, Supplementary
The in vivo studies demonstrated that R1530 has notable
antitumor activity across a broad range of human xenograft
C
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ACS Medicinal Chemistry Letters
Letter
models, with minimal toxicity, and provided compelling
support for further evaluation of R1530 in humans. R1530
disrupts normal tubulin dynamics inducing a delay in the
transition of mitosis. Because of R1530 inhibitory effects on the
checkpoint machinery, cells slip through the mitotic block
without the proper partitioning of DNA and cytokinesis.
Endoreduplication occurs, and the cells ultimately undergo cell
death via mitotic catastrophe or cellular senescence.
To provide the larger quantities of material needed for the
toxicology and clinical formulation studies, a comparison was
made of the two methods described above for the preparation
of R1530. In the convergent method, the synthesis began with
commercially available 3,4-difluoro-aniline 14, which on
reaction with 2-chlorobenzaldehyde 7 and subsequent
oxidation gave benzophenone 15 in 86% yield (Scheme 3).
triazole, diisopropylethylamine, and phosphorus oxychloride,
followed by sodium methoxide in methanol to give
iminomethyl ether 17. Slow addition of N,N-dimethyl-
acetamide dimethyl acetal (DMA-DMA, 2 equiv) to a solution
of 17 in DMF at 130 °C, followed by an additional 24 h of
heating at 130 °C, resulted in the formation of the acylated
intermediate. The DMF was removed under reduced pressure,
and the residue was treated with hydrazine in a mixture of
dichloromethane and methanol at room temperature or in
toluene at 110 °C. The crude R1530 was obtained by
precipitation, triturated with hot 1,2-difluorobenzene, then
dissolved in acetone, and filtered to remove solids. After solvent
exchange to isopropyl acetate, the addition of heptane followed
by filtration gave the title compound, R1530, in 72% yield from
16. This linear process has been successfully utilized by our
Chemical Synthesis Department to produce 3.4 kg of clinical
material with 30−35% overall yield.
a
Scheme 3. Large Scale Synthesis of R1530
In summary, further exploration of the pyrazolobenzodiaze-
pine template at the 7- and 8-positions has led to the discovery
of R1530. Additional profiling of R1530 demonstrated the
potent antiproliferative and proapoptotic activities as well as
robust in vivo efficacy. Two efficient synthetic processes were
developed to make R1530 and its derivatives, and a seven-step
synthesis was used for process chemistry with 30−35% overall
yield. R1530 was selected for further evaluation in phase I
clinical evaluations.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details for the synthesis and characterization of
R1530. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jinzi06@gmail.com (J.-J.L.), kin-chun.luk@roche.com
(K.-C.L.), or wovkuln24@verizon.net (P.M.W.).
■
a
Reagents and conditions: (a) PhBCl2/TEA/NaOH aq. (b) MnO2
Notes
(86%, two steps). (c) MeOH/NaOMe, reflux, 80 min, 97%. (d)
TsOH/iPrOH/microwave, 170 °C, 15 min, 45%. (e) DIBAH/THF/
(dppp)NiCl2, 29%. (f) BCl3/GaCl3/toluene, reflux. (g) Na-OMe/
MeOH/t-amyl alcohol, reflux (52%, two steps). (h) MeO-
COCH2NH3Cl/AcOH/iPrOH, reflux, 91%. (i) POCl3 (1.5 equiv)/
DIPEA (6.0 equiv)/Triazole (6.0 equiv)/THF, 10 °C to rt. (j)
MeOH/NaOMe (7.0 equiv)/MeOH, reflux, 18 h (98%, two steps).
(k) DMA(OMe)2 (2.0 eq, slow addition), DMF, 130 °C, 20 h. (l)
N2H4 (6.0 equiv)/L-ascorbic acid (0.02 equiv)/CH2Cl2/MeOH, rt, 20
h, or toluene, reflux (72%, two steps). 30−35% overall yield from
compound 14.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Gino Sasso for H NMR spectral analysis and NOE
■
1
studies and Vance Bell, Richard Szypula, Theresa Burchfield,
and Michael Lanyi for mass and IR spectral analysis. We thank
members of the Discovery Oncology In Vivo Section for
assistance with tumor efficacy studies, and Hong Yang and
Daisy Carvajal for cell-based assay work.
ABBREVIATIONS
■
KDR, kinase insert domain receptor, an alternative name for
VGFr2; VGFr2, vascular endothelial growth factor receptor 2;
FGFr, fibroblast growth factor receptors; PDGFr, platelet-
derived growth factor receptors; EGFr, epidermal growth factor
receptor; Chk2, checkpoint kinase 2; CDK, cyclin-dependent
kinases; TGI, tumor growth inhibition; PK, pharmacokinetics;
CL, clearance; Vss, volume of distribution; Tmax, time of
maximum concentration; Cmax, maximum concentration; AUC,
area under curve; F, measure of oral bioavilibility
Introduction of the 8-methoxy group was accomplished by the
regioselective fluoride displacement of benzophenone 15 using
sodium methoxide in refluxing methanol to give ketone 9 in
97% yield. Microwave-promoted coupling of 9 plus 1-allyl-5-
chloro-3-methyl-1H-pyrazol-4-ylamine 13 followed by depro-
tection gave R1530 in low yield for the two steps.
Alternatively, the linear route began with the Sugasawa
reaction of 14 and 2-chloro-benzonitrile 4 followed by
treatment with NaOMe in methanol gave imine 5b in 52%
yield for the two steps. Treatment of imine 5b with glycine
methyl ester hydrochloride in refluxing isopropanol-acetic acid
produced the corresponding 7-fluoro-8-methoxy-benzodiaze-
pine 16 in 91% yield. Benzodiazepine 16 was treated with 1,2,4-
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