Piperidine-containing β-arylpropionic acids as potent antagonists of αvβ3/αvβ5 integrins

Article abstract of DOI:10.1016/j.bmcl.2004.06.061

The synthesis and SAR of a new class of piperidine-based α_vβ₃/α_vβ₅ integrin antagonists is described.

Full text of DOI:10.1016/j.bmcl.2004.06.061

Bioorganic & Medicinal Chemistry Letters 14 (2004) 5227–5232
Piperidine-containing b-arylpropionic acids as potent antagonists of
avb3/avb5 integrins
a
a
a
a
Bart L. De Corte,a, William A. Kinney, Li Liu, Shyamali Ghosh, Livia Brunner,
William J. Hoekstra,a Rosemary J. Santulli,a Robert W. Tuman,a Judith Baker,a
Candace Burns,a Jef C. Proost,b Brett A. Tounge,a Bruce P. Damiano,a
Bruce E. Maryanoff,a Dana L. Johnsona and Robert A. Galemmo, Jr.a
*
aDrug Discovery, Johnson & Johnson Pharmaceutical Research and Development, Welsh & McKean Roads, Spring House,
PA 19477-0776, USA
bDrug Discovery, Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium
Received 7 May 2004; revised 18 June 2004; accepted 18 June 2004
This paper is dedicated to the memory of Barry C. Lange (deceased April 2003), who touched our lives briefly, but memorably, with his positive spirit
Abstract—The synthesis and SAR of a new class of piperidine-based avb3/avb5 integrin antagonists is described. Replacement of an
amide bond in a prototype isonipecotamide by a C–C isostere, and adjustment of the spacer length between the carboxylic acid and
basic moieties, led to low nanomolar antagonists of avb3 and/or avb5 integrins with excellent selectivity versus aIIbb3.
Ó 2004 Elsevier Ltd. All rights reserved.
Integrins are a family of heterodimeric transmembrane
glycoproteins that are involved in cell–cell interactions
and communication between cells and the extracellular
matrix. These receptors have been implicated in a vari-
ety of diseases, such as cancer, osteoporosis, restenosis,
and macular degeneration.1–6 The integrins aIIbb3, avb3,
avb5, avb6, and a5b1 recognize adhesive proteins that
contain the Arg-Gly-Asp (RGD) tripeptide sequence,7,8
which is critical for binding to the integrin extracellular
domain. Hence, selective and bioavailable nonpeptide
mimics of the RGD recognition motif have been pur-
sued in attempts to modulate integrin-mediated biologi-
cal processes, such as cell adhesion, migration, and
proliferation.1,2,4,9–15
studies, we found that replacement of the basic piper-
idine by other basic groups and exchange of the nipecot-
amide for an isonipecotamide core causes a reversal of
integrin binding selectivity.17 Whereas elarofiban is a
potent antagonist of aIIbb3 (IC50 =0.15nM) with little
activity against the avb3 integrin (IC50 >50lM), related
isonipecotamide 1 is a potent antagonist of avb3
(IC50 =19nM) with weak activity against aIIbb3
(IC50 =1.8lM). This observation prompted us to
explore the potential of the isonipecotamide scaffold
as a template for selective antagonists of the avb3
integrin.
Diverse isonipecotamide analogues were prepared via
solid-phase chemistry (Scheme 2)18 with a variety of
basic moieties and aryl substituents being introduced.
Some of the basic groups were inspired by literature re-
ports, such as tetrahydronaphthyridine,19 aminopyr-
idyl,20 and cyclic guanidines,21 which are guanidine
isosteres that have yielded potent avb3 integrin antago-
nists. Wang resin-bound Fmoc-protected b-amino acids
2 were deprotected by treatment with piperidine in
DMF and reacted with Fmoc-protected isonipecotic
acid under standard peptide coupling conditions to yield
3. After removal of the protecting group (viz. 4), the
resin-bound isonipecotamides were coupled with a variety
A drug discovery program in our laboratory that tar-
geted the platelet fibrinogen (Fg) receptor, aIIbb3
(GPIIb/IIIa), produced elarofiban (RWJ-53308), a po-
tent, selective, orally bioavailable antagonist, which
was selected for human clinical evaluation (Scheme
1).16 In the course of structure–activity relationship
Keywords: Integrin; b-Aryl propionic acids; Vitronectin.
*
Corresponding author. Tel.: +1-215-628-5513; fax: +1-215-628-
3297; e-mail: bdecorte@prdus.jnj.com
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.06.061

5228
B. L. De Corte et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5227–5232
CO2H
N
O
HN
CO2H
H
N
N
N
N
H
N
O
O
N
N
H
H
O
N
1
Elarofiban
Nipecotamide
Isonipecotamide
Binding IC50: αvβ3 = 19 nM
Binding IC50: αIIbβ3 = 0.15 nM
αvβ3 > 50,000 nM
αIIbβ3 = 1,800 nM
CO2H
Ar
O
N
H
Basic
Group
N
Scheme 1. Design of an isonipecotamide-based avb3 antagonist library.
O
Two synthetic strategies for the synthesis of the C–C
isosteres were employed. The first approach was based
on the Claisen rearrangement of a trimethylsilyl ketene
acetal derived from malonate 8 (Scheme 3).24 Boc-pro-
tected isonipecotic acid 6 was converted to piperidine
aldehyde 7,25 which was reacted with arylacetylides
to form the corresponding propargyl alcohols. After
partial reduction to the cis-olefins, the alcohols were
converted to malonates 8. Their corresponding trimeth-
ylsilyl ketene acetals rearranged smoothly on heating
and the accompanying desilylation/decarboxylation pro-
vided methyl esters 9.
O
O
O
a, b
N
H
Ar
O
N
Fmoc
FmocNH
Ar
3
2
c
O
CO2H
Ar
O
O
O
N
d, e
N
H
Ar
H
R
N
HN
The Boc-protecting group was removed under standard
conditions and the resulting piperidines were cou-
pled with different acids to yield amides 10. Hydrolysis
of the methyl ester, followed by catalytic hydro-
genation, yielded the desired C–C bioisosteres
11.
5
4
O
Scheme 2. Solid-phase synthesis of an isonipecotamide integrin
antagonist library. Reagents and conditions: (a) piperidine, DMF;
(b) Fmoc-protected isonipecotic acid, (i-Pr)2NEt, O-(7-azabenzo-
triazol-1-yl-N,N,N0,N0-tetramethyluronium
hexafluorophosphate
(HATU), DMF; (c) piperidine, DMF; (d) RCO2H, (i-Pr)2NEt, HATU,
DMF; (e) CF3CO2H, CH2Cl2.
Alternatively, the target compounds were prepared
according to Scheme 4.26 Piperidine acids 12 (n=2) were
converted into the corresponding Weinreb amides and
transformed into aryl ketones 13 via condensation with
an in situ generated aryl lithium species. Horner–Em-
mons chemistry, followed by hydrogenation and hydrol-
ysis of the Boc group, gave piperidines 14. Coupling
of 14 with a desired carboxylic acid, followed by
basic hydrolysis of the ester, provided target compounds
15.
of acids. Cleavage from the support yielded target com-
pounds 5.
Some representative compounds are depicted in Table 1.
The combination of the tetrahydronaphthyridine or
cyclic guanidine basic group with a 5-methylenedioxy-
phenyl or 3-quinolinyl substituent for Ar (5c, 5d–f) gave
the most potent avb3 integrin antagonists in the isonipe-
cotamide series. The selectivity versus aIIbb3 was varia-
ble, however. Unfortunately, the desired potency and
selectivity of these compounds was not accompanied
by an acceptable pharmacokinetic (PK) profile; in partic-
ular, the oral bioavailability of these compounds in rats
never exceeded 4% (data not shown). We hypothesized
that the poor oral bioavailability was, at least in part,
due to the amide bond at the 4-position of the piperidine
ring. On the basis of this rationale, the isonipecotamide
amide bond was replaced by a C–C isostere to reduce
polarity.
We were gratified that some target molecules, such as
11a, possessed potent avb3 integrin binding (Table 2).27
The combination of the methylenedioxyphenyl group
with the tetrahydronaphthyridine (11b) or aminopyridyl
groups (11c) resulted in considerably weaker antago-
nists. When the PK profile of some of these compounds
was evaluated, only 11b and 11c were found to exhibit
desirable oral bioavailability. A head-to-head compari-
son between C–C isostere 11c and amide 5g in a rat
PK study validated our working hypothesis that a less

B. L. De Corte et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5227–5232
Table 1. Effect of basic group and aryl substitution on integrin binding activity
5229
CO2H
Ar
O
N
H
R
N
O
Compd
R
Ar
IC50 (nM)
a
b
avb3
aIIbb3
N
5a
5b
45.7 16
25.3 12
1810 86
56.4 20
N
N
N
H
H
NH
O
O
N
N
H
H
N
N
O
O
5c
10.4 2.0
209 93
N
N
H
H
5d
5e
2.6 0.5
2.8 0.6
2850 314
79.3 15
N
H
N
N
N
N
N
N
H
H
HO
N
5f
5.5 2.4
177 3.8
N
H
N
N
H
a Inhibition of human vitronectin binding to immobilized avb3 (N P 3 when IC50 <1lM).22
b Inhibition of biotinylated Fg binding to immobilized aIIbb3 (N P 2 when IC50 <1lM).23
O
O
O
O
O
OMe
Ar
c - e
a, b
H
OH
N
N
tBoc
tBoc
N
6
8
7
tBoc
f - g
O
CO2H
Ar
CO2Me
Ar
OMe
h - i
j - k
Ar
R
N
R
N
N
tBoc
11
10
9
O
O
Scheme 3. Synthesis of C–C bioisosteres. Reagents and conditions: (a) i-BuOCOCl, MeNHOMeÆHCl, N-methylmorpholine, THF; (b) LiAlH4, Et2O;
(c) BuLi/HCCAr, THF; (d) H2, Lindlarꢀs catalyst, pyridine; (e) ClCOCH2CO2Me, Et3N, CH2Cl2; (f) NaH, TMSCl, THF; (g) heat; (h) CF3CO2H,
CH2Cl2; (i) RCO2H, (i-Pr)2NEt, HATU, DMF; (j) NaOH, 1,4-dioxane; (k) H2, Pd/C, MeOH.
polar core is conducive to an improved PK profile.
Despite the disappointing binding affinity for 11b and
11c, it is apparent that the combination of a methylene-
dioxyphenyl with less basic moiety such as
a

5230
B. L. De Corte et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5227–5232
Several truncated combinations (n=0, 1) with equiva-
( )n
( )n
Ar
a, b
CO2H
lent structural features were synthesized (Scheme 4).26
This approach furnished a compound with the desired
profile, in that 15a turned out to be a low-nanomolar
antagonist of avb3 with excellent selectivity versus aIIbb3
(Table 3). A potential benefit of 15a and 19 is their im-
proved binding potency for avb5, since dual avb3/avb5
integrin antagonists have been reported to block
tumor-induced angiogenesis.28,29
O
N
N
tBoc
tBoc
12
13
c - e
( )n
( )n
CO2H
CO2Me
f, g
We investigated the oral bioavailability of 15a in rats
and we were pleased to discover that its pharmacokine-
tic profile is quite satisfactory (Table 4). Replacement of
the methylenedioxyphenyl group with various aryl
groups (15b–f) indicated that the 3-(4-piperidinyl-
methyl)-3-arylpropionic acid scaffold is an excellent tem-
plate for the design of nanomolar inhibitors of both the
avb3 and avb5 integrins (Table 4). The oral bioavailabil-
ity of these analogues is highly dependent on the nature
of the aryl substituent.
Ar
R
O
N
Ar
HN
TFA•
15
14
Scheme 4. Alternative synthesis of C–C isosteres (n=2) and truncated
analogues (n=0, 1). Reagents and conditions: (a) i-BuOCOCl,
MeNHOMeÆHCl, NMM, THF; (b) BuLi/ArX (X=Br or I), THF;
(c) (MeO)2POCH2CO2Me, NaN(TMS)2, THF; (d) H2, Pd/C, MeOH;
(e) CF3CO2H, CH2Cl2; (f) RCO2H, (i-Pr)2NEt, HATU, DMF; (g)
NaOH, 1,4-dioxane.
tetrahydronaphthyridine is useful for obtaining oral bio-
availability. We realized that the spacer length between
the basic moiety and the carboxylic terminus was not
optimal, as it is greater than the length generally con-
tained in potent antagonist series reported in the litera-
ture. Consequently, we tried to regain integrin affinity
while maintaining good bioavailability by reducing this
distance.
In summary, we have identified a novel series of potent
avb3/avb5 integrin antagonists based on a piperidine
template. Replacement of an amide bond in isonipe-
cotamide lead 5g by a C–C isostere, and adjustment of
the spacer length between the carboxylic acid and
basic moieties, led to low-nanomolar inhibitors of the
avb3 and avb5 integrins with excellent selectivity versus
aIIbb3.
Table 2. Structure–activity relationship of selected C–C isosteres 11a–c and comparison with isonipecotamide 5g
CO2H
CO2H
Ar
O
O
N
H
N
R
N
O
N
N
H
5g
11a-c
Ar
O
O
Compd
R
IC50 (nM)
Rat PKc
a
b
avb3
aIIbb3
Oral
F (%)
t1/2 (po)
(h)
Cl (iv)
(mg/kglMh)
AUC (po)
(lMh)
HO
N
O
O
11a
11b
1.7 0.5
1578 1056
4362 2558
2.6
88
5.4
0.04
0.09
21.2
304
N
N
H
H
O
O
142 27
3.0
N
H
N
O
O
11c
5g
233 101
21.7 6.6
10,882 3670
15,719 1319
96
6.6
6.7
0.2
142
7.9
N
N
H
––
––
2.4
0.09
a Inhibition of human vitronectin binding to immobilized avb3 (N P 3 when IC50 <1lM).22
b Inhibition of biotinylated Fg binding to immobilized aIIbb3 (N P 3 when appropriate).23
c PK experiments were performed in rats dosed po (10mg/kg, N=4) versus iv (2mg/kg, N=4). The drug levels in plasma were determined by LC/MS.
Oral dosing was done in 5% dextrose in water at pH2.

B. L. De Corte et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5227–5232
Table 3. Effect of spacer length on integrin binding affinity
5231
(CH2)n
CO2H
O
H
(CH2)m
N
N
N
O
O
Compd
m
n
IC50 (nM)
a
b
a
avb3
aIIbb3
avb5
16
17
18
15a
19
20
1
1
2
2
3
3
0
2
0
1
0
1
281c
>10,000c
>10,000
775c
75 16
28.1
405 126
95.7 23
2.3 0.9
33.5 6.3
220 95
8
6195 1155
2515 295
4030 430
4260 1660
1.1 0.2
1.9 0.2
20.6 5.8
a Same as Table 2.
b Same as Table 2.
c N=1.
Table 4. Structure–activity relationship of 15a–f
CO2H
N
Ar
N
N
15a-f
H
O
Compd Ar
IC50 (nM)
Rat PKc
a
a
b
avb3
avb5
aIIbb3
Oral F (%) t1/2 (po) (h) Cl (iv) (mg/kglMh) AUC (po) (lMh)
O
15a
1.1 0.2
2.3 0.9 2515 295
31
2.1
0.1
97
O
3-Fluorophenyl
3-Pyridyl
15b
15c
15d
1.0 0.2
0.8 0.1
2.8 0.1 >10,000
1.7 0.3 6610 2850
0.7 0.2 965 75
14
0
1.7
ndd
2.6
0.5
1.1
2.7
ndd
<0.1
2-Me-pyrimidin-5-yl 0.7 0.3
4
10.4
OMe
15e
1.5 0.8
4.6 1.7 1470 369
1
ndd
1
0.1
N
N
OMe
2-Naphthyl
15f
1.9 0.6 24.5 6.5 >10,000
47
5.65
0.02
286
a Same as Table 2.
b Same as Table 2.
c Same as Table 2.
d nd=not determined.
6. Duggan, M. E.; Hutchinson, J. H. Expert Opin. Ther.
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