Convergent, parallel synthesis of a series of β-substituted 1,2,4-oxadiazole butanoic acids as potent and selective α vβ3 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2005.11.008

We describe a series of 1,2,4-oxadiazoles, which are potent antagonists of the integrin α_vβ₃ and, in addition, show selectivity relative to the other β₃ integrin α_IIbβ₃. In whole cells, the majority o

Full text of DOI:10.1016/j.bmcl.2005.11.008

Bioorganic & Medicinal Chemistry Letters 16 (2006) 839–844
Convergent, parallel synthesis of a series of b-substituted
1,2,4-oxadiazole butanoic acids as potent and
selective avb3 receptor antagonists
Mark L. Boys,a,* Lori A. Schretzman,b Nizal S. Chandrakumar,b Michael B. Tollefson,c
Scott B. Mohler,b Victoria L. Downs,a Thomas D. Penning,b Mark A. Russell,b
John A. Wendt,a Barbara B. Chen,b Heather G. Stenmark,b Hongwei Wu,b
Dale P. Spangler,b Michael Clare,c Bipin N. Desai,b Ish K. Khanna,b Maria N. Nguyen,a
Tiffany Duffin,b V. Wayne Engleman,c Mary Beth Finn,c Sandra K. Freeman,c
Melanie L. Hanneke,c Jeffery L. Keene,c Jon A. Klover,c G. Allen Nickols,c
Maureen A. Nickols,c Christina N. Steininger,c Marisa Westlin,c William Westlin,c
Yi X. Yu,b Yaping Wang,b Christopher R. Daltonb and Sarah A. Norringb
aDepartment of Chemistry, PfizerGlobal Research and Development, 2800 Plymouth Rd., Ann Arbor, MI 48105, USA
bDepartment of Medicinal Chemistry, PfizerGlobal Research and Development, 4901 Searle Parkway, Skokie, IL 60077, USA
cDepartments of Medicinal Chemistry, Discovery Pharmacology and Oncology, PfizerGlobal Research and
Development, 700 Chesterfield Village Parkway, Chesterfield, MO 63198, USA
Received 22 September 2005; revised 3 November 2005; accepted 3 November 2005
Available online 17 November 2005
Abstract—We describe a series of 1,2,4-oxadiazoles, which are potent antagonists of the integrin avb3 and, in addition, show selec-
tivity relative to the other b3 integrin aIIbb3. In whole cells, the majority of these analogs also demonstrated modest selectivity
against other av integrins such as avb1 and avb6.
Ó 2005 Elsevier Ltd. All rights reserved.
The integrin avb3 is a non-covalently linked, heterodi-
meric transmembrane receptor, which is found on the
surface of activated endothelial cells, smooth muscle
cells, and many tumor cells. The avb3 receptor recogniz-
es the arginine–glycine–aspartic acid (RGD) tripeptide
sequence contained within various extracellular matrix
proteins. Through this interaction endothelial cells and
tumor cells are able to unite with a wide variety of extra-
cellular matrix components such as vitronectin, fibro-
nectin, fibrinogen, thrombospondin, osteopontin, bone
sialoprotein, and denatured collagen.1 Antagonists of
avb3 have been demonstrated to inhibit angiogenesis,
the process of new blood vessel growth from pre-existing
vasculature, and thereby have potential utility in inhib-
iting tumor growth.2 The avb3 receptor is also the preva-
lent integrin found on the surface of osteoclasts, which
are responsible for cellular attachment and subsequent
bone resorption.3 Antagonists of avb3 have been shown
to inhibit bone loss in animal models of osteoporosis4
and have shown efficacy in animal models of rheuma-
toid arthritis.5 In addition, avb3 is believed to play a sig-
nificant role in several other pathophysiological
conditions, including restenosis after angioplasty6 and
ocular neovascularization.4,7 Antagonists of this integrin
may prove to be beneficial in the treatment of these
diverse disease states.
Peptidomimetic avb3 antagonists based on the RGD
sequence, such as SC-68448, which demonstrated anti-
tumor efficacy in a mouse Leydig cell tumor model8 have
been reported previously. Other avb3 antagonists in
which the central glycine linker have been replaced with
Keywords: Integrin; Vitronectin; avb3; Antagonist; 1,2,4-Oxadiazole;
RGD; Peptidomimetic.
*
Corresponding author. Tel.: +1 734 622 7248; fax: +1 734 622
2440; e-mail: mark.l.boys@pfizer.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.11.008

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M. L. Boys et al. / Bioorg. Med. Chem. Lett. 16 (2006) 839–844
non-peptidic moieties have subsequently been reported.
In addition, reduced basicity guanidine isosteres have
been incorporated. These efforts have resulted in com-
pounds with improved pharmacokinetic properties.9
which was known to be an effective guanidine mimetic
when applied to avb3 antagonists.12 Reaction of the
hydroxyamidine 1 with 3-substituted or 3,3-disubstitut-
ed glutaric anhydrides 2 allowed construction of the
1,2,4-oxadiazole ring with concomitant introduction of
a substituted butanoic acid chain (Scheme 1).13 This al-
lowed for the rapid parallel synthesis of a series of ana-
logs in racemic form. The limiting factor was thus the
accessibility of the glutaric anhydrides. Fortunately,
we were able to exploit various established methods to
generate these intermediates (Scheme 2).14
O
H
H
H2N
N
N
N
CO2H
Cl
H
SC-68448
NH
O
Cl
In particular, the condensation of an aromatic aldehyde
with ethyl acetoacetate mediated by piperidine and sub-
sequent basic digestion of the resulting carbocyclic inter-
mediate to give a 3-aryl glutaric diacid (Scheme 2)
proved particularly convenient.15 The diacids could
readily be converted to the cyclic anhydrides by heating
with excess acetic anhydride. Other substituted glutaric
anhydrides were prepared via established procedures
We now report some of our own efforts directed toward
non-peptidic analogs.10 We chose to incorporate the
readily constructed 1,2,4-oxadiazole ring, a known es-
ter/amide isostere, as a central core. The synthesis
exploited the hydroxyamidine intermediate 1.11 The
1,8-tetrahydronaphthyridine moiety was incorporated,
H
N
NH2
N
NH2
OH
N
O
a,b,c
+
CN
N
CHO
1
R2
R1 R2
R1
H
N
N
d
N
O
1
+
CO2H
N
O
O
O
3
2
Scheme 1. Reagents and conditions: (a) i—Proline, EtOH, D, ii—isomer separation (b) H2/Pd; (c) NH2OH, EtOH, D; (d) 1,4-dioxane, D.
Aryl
O
d, e, f, g, c
or h, i, g, c
a, b, c
Aryl Br
Aryl CHO
O
O
R
N
S
R
N
j
S
a, b, c
S
R
NH2
CHO
O
O
O
CO2Et
CO2Et
CHO
MeO
k, e, f
l, m, g, n
MeO
MeO
MeO
O
O
O
R1 R2
R1 R2
o
O
O
O
O
Scheme 2. Representative methods for forming 3-substituted glutaric anhydrides. Reagents and conditions: (a) ethyl acetoacetate, piperidine; (b) i—
NaOH, H2O, EtOH, D, ii—HCl; (c) Ac2O, D; (d) ethyl acrylate, Pd(OAc)2, P(o-tol)3, Et3N; (e) diethyl malonate, NaOEt, EtOH; (f) DMSO, H2O, NaCl,
D; (g) i—NaOH, ii—HCl; (h) MeO2CCHCHCH2CO2Me, Pd(OAc)2, P(o-tol)3, Et3N; (i) H2, Pd; (j) CHCl(CHO)2, MgCO3; (k) EtO2CCHPO(OEt)2,
MeCN, DBU, LiCl; (l) AcOH, H2O; (m) (EtO)2POCN2COCH3, K2CO3, EtOH; (n) i—NaOH, ii—(CF3CO)2O, 50 °C; (o) See Ref. 14.

M. L. Boys et al. / Bioorg. Med. Chem. Lett. 16 (2006) 839–844
841
Table 2. SPRA data for b,b-di-substituted analogs
or as outlined in Scheme 2. For examples 13 and 14–28,
the single enantiomers (S) were prepared via coupling of
the resolved glutaric half ester with the hydroxyami-
dines. The resolved half ester was obtained by chroma-
tographic separation of the enantiomers or via an
enzymatic hydrolysis of the glutaric di-ester.10
R2
H
N
R1
N
N
O
CO2H
N
Compound
R1
R2
IC50 (nM)a
A series of b-substituted 1,2,4-oxadiazolyl butanoic
acids were prepared (Table 1) and tested in both the
avb3 and aIIbb3 solid-phase receptor binding assays
(SPRA).4 Most analogs demonstrated at least 100-fold
selectivity over the related platelet integrin, aIIbb3. Intro-
duction of a b-substituent imparted considerable poten-
cy with a methyl group giving an order of magnitude
increase in potency over a hydrogen atom (compounds
4 and 5). Aromatic, substituted aromatic, and heteroa-
romatic substituents gave the best potency (compounds
7–17). The quinoline and benzoxazole analogs (11, 14)
gave sub-nanomolar activity, avb3 for although the
selectivity versus aIIbb3 was decreased for compound 11.
avb3 SPRA
aIIbb3 SPRA
18
19
20
21
Me
Ph
Me
Me
Me
20
116
12,607
35,774
950
3-Pyridyl
–(CH2)4–
3.6
9.5
8130
a Average of at least three determinations.
Table 3. SPRA data for alternate guanidine mimetic analogs
O
O
N
R
CO2H
N
O
A number of b,b-disubstituted analogs were also pre-
pared. Data for a selection of these analogs are shown
in Table 2. In general, the potency was reduced from
the mono-substituted analogs. However, the 3-pyridyl,
Compound
R
IC50 (nM)a
avb3SPRA
aIIbb3 SPRA
H
N
N
Table 1. SPRA data for b-substituted analogs
22
1.7
Not tested
H
N
R
N
N
N
O
CH3
CO2H
N
H
N
N
23
H3C
N
2.1
2.4
278
126
Compound
R
IC50 (nM)a
H
N
24b
avb3 SPRA
aIIbb3 SPRA
4
5
6
7
8
9
H
Me
160
12
32,466
9298
1217
747
H
N
N
25b
26b
2.0
1.1
91
64
C„CH
Ph
8.7
1.8
1.75
1.6
CH3
3-Fluoro-Ph
3-Pyridyl
419
474
H
N
N
H3CO
10
11
1.0
187
18
N
N
OCH3
H
N
0.65
N
N
27b
0.78
0.26
17
22
12
13b
14
15
16
17
2.1
224
27
O
O
O
N
0.4
H
N
O
N
28b
0.50
1.28
1.43
1.2
65.4
423
168
216
O
N
S
N
H3C
S
a Average of at least three determinations.
b Single enantiomer (S).
N
S
N
N
methyl analog 20 did retain low single digit potency
for avb3 and was approximately 300-fold selective for
aIIbb3.
a Average of at least three determinations.
b Single enantiomer (S).

842
M. L. Boys et al. / Bioorg. Med. Chem. Lett. 16 (2006) 839–844
Table 4. Cell assay selectivity data
pKa of the guanidine surrogate was, in part, contribut-
ing to the increased potency of these analogs.
Compound
IC50 (nM)a
avb1
293 cell
avb3
293 cell
avb5
293 cell
avb6
HT29 cell
Selected analogs were also tested for binding to avb1-,
avb3-, and avb5-expressing 293 cells16 and avb6-express-
ing HT29 cells10 to probe selectivity against other av
integrins (Table 4). In general, whole cell avb3 potencies
were similar to those obtained in the SPRA. The avb1
and avb5 potencies were slightly lower than, but mostly
within an order of magnitude of avb3, while avb6 poten-
cies were significantly less (generally 500- to 1500-fold).
b
b
b
6
8
4.0
1.1
4.0
3.7
6240
3730
9
0.77
0.63
0.65
0.32
0.60
3.2
3.3
b
2420
3020
12
13
14
16
23
27
28
9.7
2.6
1.7
b
2660
486
2.7
b
1.2
1590
b
b
b
16
>10,000
4360
2670
0.74
0.62
4.6
2.9
Representative synthetic protocols for analogs 22–28 are
shown in Schemes 3 and 4 . For analogs 22–24, alternate
hydroxyamidines were prepared (Scheme 3) and were
combined with the obligatory glutaric anhydride as in
Scheme 1. For analogs 25–28, a reductive amination of
the aldehyde intermediate 29 with a requisite aminopyri-
dine offered an alternate and efficient mode of synthesis
(Scheme 4).
a Average of at least three determinations.
b Not tested.
The 1,8-tetrahydronaphthyridine moiety was clearly an
effective guanidine mimetic for these oxadiazole based
avb3 antagonists, which is in line with the findings of
other researchers.12 Some structural variation of this
part of the molecule was investigated however to deter-
mine if further optimization were possible. A selection
of guanidine mimetic variants is shown in Table 3.
The b-substituent was held constant as the 3,4-methy-
lenedioxyphenyl group.
The rat pharmacokinetics (PK) of some representative
examples is shown in Table 5. In general, the com-
pounds had high bioavailability with short t1/2 and mod-
erate clearance. The thiomorpholine analog 28 had
relatively high clearance probably due to the higher
pKa. The analog 16 containing the cyclopropylthiazole
b-substituent had the highest oral exposures in this ser-
ies, while retaining reasonable potency. It was consid-
ered that improved half-life in rat would probably be
needed in order to translate to a suitable half-life in hu-
man for once or twice a day dosing.
The aminopyridine 24 and reversed aminopyridine 23
were slightly less potent than the corresponding tetra-
hydronaphthyridine analog 13. This may be due at least
in part to increased conformational freedom. Substitu-
tion of electron-donating groups on or within the pyri-
dine or naphthyridine nucleus tended to increase
potency with the 4-thiomorpholine-substituted analog
28 being notable. We speculate that an increase in the
In summary, we have developed a series of readily acces-
sible 1,2,4-oxadiazole butanoic acid analogs, and by
appropriate substitution at the b-position and by the
H
N
H
N
H
N
H2N
N
Br
N
Br
N
N
NH2
OH
a
c
b
CN
N
Boc
H
N
O
N
O2N
HO
N
O2N
N
N
N
N
g,h
d,e
f
i, j
N
EtO2C
N
Boc
N
H
N
H
N
N
NH2
N
OH
N
k,l,m
c
CN
N
N
OH
N
N
H
N
H
N
N
NH2
OH
N
O
n,o
p
O
c
CN
Br
CN
N
O
Scheme 3. Synthesis of alternate hydroxyamidines for the preparation of compounds 22–24. Reagents: (a) NaH, MeI; (b) NC(CH2)3ZnBr,
Pd(PPh3)4; (c) NH2OH; (d) (CF3SO2)2O, Et3N; (e) MeNHCH2CO2Et; (f) H2, Pd/C; (g) LiAlH4; (h) Boc2O, Et3N; (i) LDA, diethylcarbonate; (j)
LiBH4; (k) Ph3P, imidazole, I2; (l) ethylcyanoacetate, NaH, DMF; (m) KOH, ethylene glycol, D; (n) NaCN, DMF; (o) p-TsOH, Me2CO, H2O,
NaIO4; (p) 2-aminopyridine, NaBH(OAc)3.

M. L. Boys et al. / Bioorg. Med. Chem. Lett. 16 (2006) 839–844
843
O
O
O
O
O
OH
N
O
N
O
c,d
a,b
O
Cl
CO2H
THPO
NH2
THPO
THPO
100 oC
N
O
O
N
NH2
O
O
N
N
O
O
R
e
25-28
CO2Me
CO2Me
HO
O
f,g
N
N
29
N
NH2
N
NH2
h
N
X
Cl
Scheme 4. Synthesis of compounds 25–28. Reagents and conditions: (a) NaCN, NaI, DMF; (b) NH2OH; (c) MeI, K2CO3; (d) p-TsOH, MeOH; (e)
TPAP, NMO, sieves; (f) NaBH(OAc)3, R=Me, OMe, morpholine, thiomorpholine; (g) LiOH; (h) morpholine or thiomorpholine (X=O, S);
dimethylacetamide, 200 °C, Microwave.
Table 5. Rat PK data for select analogs
9, 1271; (d) Mitjans, F.; Meyer, T.; Fittschen, C.;
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Compound
F
t1/2
AUC (po)/Dose Cl
(h lg/mL/
Vz
(mL/kg)
(%) (h)
(mL/
min/kg)
*
mg/kg)
10
11
12
13
16
22
28
100 1.1
66 1.1
63 1.2
95 1.4
96 1.8
1.91
0.60
0.97
1.50
3.05
12.0
19.1
17.3
10.9
5.56
18.2
78
694
622
803
733
497
447
897
3. Nakamura, I.; Pilkington, M. F.; Lakkakorpi, P. T.;
Lipfert, L.; Sims, S. M.; Dixon, S. J.; Rodan, G. A.;
Duong, L. T. J. Cell Sci. 1999, 112, 3985.
77 0.93 0.71
29 0.40 0.06
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Calculated from 5 mg/kg IV and 10 mg/kg po dosing.
incorporation of an appropriate guanidine mimetic have
obtained a number of analogs with low to sub-nanomo-
lar avb3 potency and 100-fold selectivity over aIIbb3. In
general, this class of molecules shows good oral bio-
availability with select analogs showing promising phar-
macokinetic properties. Further development of the
SAR along with improvements in the in vivo character-
istics of this series of heterocyclic compounds will be
reported in due course.
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