Synthesis and SAR of N-substituted dibenzazepinone derivatives as novel potent and selective αVβ3 antagonists

Article abstract of DOI:10.1016/S0960-894X(01)00773-9

Synthesis and SARs of new integrin α_Vβ₃ antagonists based on an N-substituted dibenzazepinone scaffold are described. Variation of spacer and guanidine mimetic led to potent compounds exhibiting an IC₅₀ towards α_Vβ₃ in the nanomolar range, high selectivity versus integrin α_IIbβ₃ and efficacy in functional cellular assays.

Full text of DOI:10.1016/S0960-894X(01)00773-9

Bioorganic & Medicinal Chemistry Letters 12 (2002) 441–446
Synthesis and SAR of N-Substituted Dibenzazepinone Derivatives
as Novel Potent and Selective ꢀVꢁ3 Antagonists
Andreas Kling,a,* Gisela Backfisch,a Jurgen Delzer,a Herve Geneste,a Claudia Graef,a
b
Uta Holzenkamp,a Wilfried Hornberger,a UdoE. W. Lange, Arnulf Lauterbach,a
Helmut Mack,a Werner Seitzb and Thomas Subkowskia
aKnoll GmbH, D-67008 Ludwigshafen, Germany
bBASFAG, D-67056 Ludwigshafen, Germany
Received 24 September 2001; revised 29 October 2001; accepted 14 November 2001
Abstract—Synthesis and SARs of new integrin aVb3 antagonists based on an N-substituted dibenzazepinone scaffold are described.
Variation of spacer and guanidine mimetic led to potent compounds exhibiting an IC50 towards aVb3 in the nanomolar range, high
selectivity versus integrin aIIbb3 and efficacy in functional cellular assays. # 2002 Elsevier Science Ltd. All rights reserved.
Integrins are a widely expressed family of heterodimeric
transmembrane receptors mediating cell–cell and cell–
matrix adhesion, migration and signaling. They are
formed by various combinations of the currently known
17 a- and nine b-subunits which determine affinity and
specificity towards different extracellular adhesive
matrix proteins like fibrinogen, fibronectin, vitronectin,
osteopontin and laminin.1 Pharmacological modulation
of integrin mediated processes in general is of consider-
able interest,2 and especially the platelet fibrinogen
receptor aIIbb3 has attracted much interest in the search
for new antithrombotic agents.3
diseases involving neovascularization such as rheuma-
toid arthritis,12 tumor-induced angiogenesis13 and
metastasis.14
Like many integrins aVb3 recognizes the tripeptide
sequence RGD as common binding motif in its target
proteins.15 In early studies Kessler et al. disclosed cyclic
RGD peptides as selective aVb3 antagonists,16 and
deduced a general model for inhibitors suggesting a fixed
alignment of a basic as well as an acidic group (distance
between 650 and 700 pm) separated by a spacer unit. In
the meantime several groups have reported non-peptidic
aVb3 inhibitors employing various scaffolds.17,18
More recently, the integrin aVb3, the so-called vitro-
nectin receptor, has received increasing attention. aVb3
is expressed on proliferative endothelial cells and
smooth muscle cells, on macrophages, on activated pla-
telets and on metastatic tumor cells, and was shown to
be involved in bone resorption by osteoclasts, migration
of activated endothelial and vascular smooth muscle
cells, angiogenesis and tumor progression.4ꢀ6 Mono-
clonal anti-integrin aVb3 antibodies, peptidic and non-
Herein we describe the synthesis of new aVb3 inhibitors
based on an N-substituted dibenzazepinone core. We
alsopresent the structure–activity relationship (SAR) for
this class of compounds derived from modification of the
spacer between core and guanidine part and variation of
the guanidine pharmacophore. Selected examples were
examined for functional efficacy in cellular assays,
metabolic stability and resorption in the Caco-2 model.
peptidic antagonists already have shown beneficial
7ꢀ9
effects in vitroand in vivo.
Therefore it is expected
that selective aVb3 antagonists offer new therapeutic
opportunities for the treatment of several human
pathologies like osteoporosis,10 restenosis after percuta-
neous transluminal coronary angioplasty (PTCA)11 and
*Corresponding author. Tel.: +49-621-60-40879; fax: +49-621-589-
68916; e-mail: andreas.kling@abbott.de
Scheme 1. Design of dibenzazepinone based aVb3 antagonists.
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00773-9

442
A. Kling et al. / Bioorg. Med. Chem. Lett. 12 (2002) 441–446
Scheme 2. Reagents and conditions: (a) NaN3, H2SO4 (85%); (b) methyl diethylphosphonoacetate, NaH, DMF (70%); (c) NaH, BrCH2CO2tBu,
DMF/60 ꢁC (83%); (d) H2, Pd/C; CH3OH/120 bar, 50 ꢁC; (e) TFA, CH2Cl2 (56% from 3); (f) R-NH2, EDC or HATU, DIPEA, CH2Cl2, DMF/
0 ꢁC–rt; (g) LiOH, dioxane/H2O 4:1.
Scheme 3. Reagents and conditions: (a) DPPA, Et3N, LiOtBu, toluene
(65%); (b) HCl/dioxane (60%); (c) thiocarbonyldiimidazole, imi-
dazole, 1,2-phenylenediamine, CH3CN (85%); (d) HgO (yellow),
cat. S, EtOH; (e) HBr, HOAc (90% from 9).
Scheme 4. Reagents and conditions: (a) ethylene oxide, LDA, THF
(40%); (b) (COCl)2, DMSO, Et3N, CH2Cl2 (55%); (c) N-[4-(amino-
methyl)phenyl]-N0-benzylurea,26 cat. HCl, NaBH3CN, CH3OH (20%);
(d) NaOH, CH3OH/H2O/80 ꢁC (79%); (e) 4-(4-nitrophenyl)butyl
methanesulfonate, NaH, DMF/75ꢁC (40%); (f) H2, Pd/C, EtOH/
EtOAc (92%); (g) benzylisocyanate, Et3N, DMF (6%); (h) KOH,
CH3OH (90%); (i) 4-nitrobenzyl bromide, NaH, DMF; (k) H2, Pd/C,
CH3OH; (l) benzylisocyanate, Et3N, DMF; (m) KOH, CH3OH (6%
from 11).
Based on published data we established a pharmaco-
phore model as 3D-template for the assessment of novel
aVb3 antagonists which was used to design and apply
various new scaffolds in the synthesis of aVb3 antago-
nists. Comparison of aVb3 antagonists comprising a tri-
cyclic core19 and Darenzepine, a compound which had
been in development at Knoll/BASF Pharma,20 promp-
ted us to examine the dibenzazepinone moiety as a new
scaffold for integrin antagonists. Compound 1 was pre-
pared as first example of this series, and its affinity in the
mM range (Scheme 1) encouraged us to investigate this
type of structure further.
Curtius degradation and cleavage of Boc led to com-
pound 8 in high yield. Conversion into the aminobenz-
imidazole24 and deprotection using HBr in acetic acid
afforded compound 10.
Derivatives with modified acetamide linker were pre-
pared as outlined in Scheme 4. Alkylation of 11 using 4-
(4-nitrophenyl)butyl methanesulfonate25 and introduc-
tion of the benzyl urea after hydrogenation of the nitro
group afforded alkyl analogue 36 (Table 4). Reaction of
11 with ethyleneoxide gave alcohol 12, which was con-
verted into the corresponding amino and ether deriva-
tives 34 and 35 as described (Scheme 4).
Scheme 2 highlights the general synthesis of dibenzaze-
pinone based derivatives. Starting from anthraquinone,
Schmidt rearrangement and Wittig–Horner olefination
gave methyl (6-oxo-5,6-dihydro-11H-dibenzo-[b,e]aze-
pin-11-ylidene)-acetate 2. Subsequent N-alkylation,
hydrogenation and cleavage of the t-butyl ester yielded
5 as central intermediate, which was converted into the
final products by coupling with various building blocks
comprising the desired guanidine mimetics and sub-
sequent saponification.21
The N-substituted dibenzazepinone derivatives descri-
bed in this communication feature a stereogenic center,
and in addition inversion of the bis-annelated azepinone
was found to be hindered.27 Therefore compounds 1
and 13–39 were obtained as diastereomeric mixtures. In
the case of compounds 28 and 32 separation of diaster-
eomers was performed via column chromatography;
however, interconversion was observed within 24–48 h
at room temperature which prevented us from studying
the isomers separately. The screening results presented
in this paper therefore refer to the corresponding mix-
tures of diastereomers.
The building blocks carrying the guanidine pharmaco-
phores applied in the synthesis were prepared according
tomethods already described in the literature. 22 Scheme
3 depicts the preparation of N-[4-(aminomethyl)cyclo-
hexyl]-1H-benzimidazol-2-amine as an example. Starting
from
Z-protected
trans-aminomethylcyclohexane-
carboxylic acid 7,23 introduction of the amino group via

A. Kling et al. / Bioorg. Med. Chem. Lett. 12 (2002) 441–446
443
Compounds 13–39 were evaluated regarding aVb3 affi-
Table 1. Effect of spacer variation within the benzimidazole series
nity via competitive ELISA using vitronectin as natural
ligand.21 Compounds displaying IC50 values >10 mM
were considered as ‘not active’.
Table 1 displays SAR data on the influence of both
spacer structure and length and benzimidazole as gua-
nidine mimetic. The corresponding benzyl derivative 15
displayed the highest affinity within the benzimidazole
series. Elongation to phenethyl (16) or replacement by
pyridylmethyl (17) resulted in a 3- to 5-fold reduction in
potency. Incorporation of phenyl (14) o rmeta-sub-
stituted benzyl (18) led toa dramatic decrease in activity
which we consider as a result of alteration in spacer
orientation leading to an unfavorable alignment of
acidic and basic groups. Replacement of benzyl by
thienyl resulted in retention of activity for the 2,4-sub-
stituted thienyl derivative (19) and a 5-fold decrease for
the 2,5-thienyl analogue (20), whereas introduction of
the 2,4-substituted thiazole (21) led to about 10-fold
decrease in potency.
Compd
Spacer
aVb3 ELISA IC50, mMa
13
1.0
14
15
16
17
18
19
20
21
5.0
0.074
0.38
0.2
Based on these results we started to investigate SAR of
the guanidine pharmacophore employing either the 2,4-
thienyl or the benzyl residue as spacer (Tables 2 and 3).
10
Table 2 presents the results obtained in the thienyl ser-
ies. Only the pyridylaminomethyl derivative 23 showed
an activity comparable to benzimidazole 19, whereas the
aza-benzimidazole analogue 22 and the amidine 24
exhibited 5- and 10-fold reduction in activity, respectively.
0.1
0.5
Table 3 summarizes the results obtained employing the
benzyl spacer in combination with different guanidine
mimetics. Introduction of additional substituents into
the benzimidazole moiety of 19 led toa decrease in
potency (25, 26), whereas the use of guanidine itself as
pharmacophore (27) showed retained activity. In line
with recent studies28 we found about 4-fold enhanced
potency upon incorporation of benzyl urea as non-basic
guanidine mimetic (28). Exchange of nitrogen in com-
pounds 29–31 resulted in a dramatic loss of potency and
proved both nitrogens to be essential in the urea part.
Highest activity in this series was found using 2-amino-
benzimidazole as guanidine mimetic; compound 32 dis-
played an IC50 of 7.3 nM. To our surprise, the
corresponding 2-aminopyridine 33 showed a dramatic
reduction in activity, which is in contrast to our experi-
ences in using this guanidine mimetic in another series
of aVb3 antagonists.29
1.0
aValues are means of three experiments; intra-assay variation <10%,
inter-assay variation < factor 2.
Table 2. 2,4-Disubstituted thienyl analogues
Compd
R
aVb3 ELISA IC50, mMa
19
0.1
Table 4 presents the SAR with regard tothe acetamide
spacer in compound 28. Compounds 34–36 showed a
dramatic loss in potency; similar results were obtained
by elongation to the analogous propionyl amide (data
not shown). These findings clearly demonstrate an
absolute requirement for the acetamide linkage in this
part of the structure.
22
23
24
0.5
0.22
1.0
In view of the results obtained we aimed at further
optimization using the aminobenzimidazole as guani-
dine pharmacophore (Table 5). Replacement of the
benzyl residue by linear C4- and C5-alkyl (37, 38) led to
aValues are means of three experiments; intra-assay variation < 10%,
inter-assay variation < factor 2.

444
A. Kling et al. / Bioorg. Med. Chem. Lett. 12 (2002) 441–446
Table 4. Acetamide modification
Table 3. Influence of the guanidine pharmacophore
Compd
Spacer
aVb3 ELISA IC50, mMa
Compd
R
aVb3 ELISA IC50, mMa
28
0.023
15
0.074
34
35
36
na
na
10
25
26
27
28
29
30
31
32
33
0.62
0.22
0.084
0.023
10
aValues are means of three experiments; intra-assay variation < 10%,
inter-assay variation < factor 2 (na=not active).
Table 5. Spacer modification within aminobenzimidazole series
10
na
Compd
Spacer
aVb3 ELISA IC50, nMa
0.007
5.0
32
7.3
37
38
-(CH2)4-
-(CH2)5-
14.9
12.9
aValues are means of three experiments; intra-assay variation < 10%,
inter-assay variation < factor 2.
na, not active.
39
1.6
a 1.5- and 2-fold reductions of activity, respectively.
Compound 39 showed an IC50 of 1.6 nM and thus
represents the most potent derivative within the whole
dibenzazepinone series obtained so far.
aValues are means of three experiments; intra-assay variation < 10%,
inter-assay variation < factor 2.
Specificity versus aIIbb3 was examined routinely for
compounds displaying an IC50 aVb3 < 100 nM. All
compounds discussed in this paper showed at least
1000-fold selectivity.
and primary human smooth muscle cell migration. The
observation that in vitro potencies were not fully reflec-
ted in cellular adhesion assays has already been reported
for other aVb3 antagonists.31 Both 32 and 39 displayed
good absorption in the Caco-2 model32 and satisfactory
metabolic stability versus human liver microsomes.
Pharmacokinetic studies will show whether these com-
pounds are suitable for efficacy testing in in vivo models.
Compounds 32 and 39, which had been identified as
most potent representatives from this series, were sub-
mitted tofurther characterization with respect tospeci-
ficity versus other integrins, potency in functional
cellular assays and early ADME (Table 6). Both deri-
vatives exhibited high selectivity versus integrin a5b1
and a4b1, and medium to high efficacy in inhibition of
recombinant aVb3 transfected CHO-K1 cell adhesion
In summary, we have shown that the N-substituted
dibenzazepinone scaffold can be successfully employed
in the synthesis of new integrin aVb3 antagonists. SARs
involving spacer and guanidine pharmacophore were

A. Kling et al. / Bioorg. Med. Chem. Lett. 12 (2002) 441–446
445
Table 6. Profile of compounds 32 and 39
Compd aVb3/VN ELISAa
IC50, nM
a
IIbb3 /Fg ELISAa
IC50, nM
a5b1/FNb
a4b1/FNb
aVb3/OPN adhesionb SMC migrationb
Caco-2
permeation assay
Pappc, cm/sꢂ10ꢀ6
inh. @ 10ꢀ5
M
inh. @ 10ꢀ5
M
IC50, nM
inh. @ 10ꢀ5
(%)
M
32
39
7.3
1.6
>100,000
>100,000
na
na
na
na
100
40
67
100
1.6
2.7
aValues are means of three experiments; intra-assay variation < 10%, inter-assay variation < factor 2.
bCell adhesion and migration: values are means of four experiments; intra-assay variation < 20%, inter-assay variation < factor 2.
cPapp=apparent permeability coefficient,30 n=2, intra-assay variation < 20%. na, not active; VN, vitronectin; FN, fibronectin; Fg, fibrinogen;
OPN, osteopontin.
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