Non-peptide αvβ3 antagonists. Part 7: 3-Substituted tetrahydro-[1,8]naphthyridine derivatives

Article abstract of DOI:10.1016/j.bmcl.2003.11.036

A series of 3-substituted tetrahydro-[1,8]naphthyridine containing α_vβ₃ antagonists was prepared. A comparison of their in vitro IC₅₀ values to the electron properties of the 3-substituents revealed a good linear Hammett c

Full text of DOI:10.1016/j.bmcl.2003.11.036

Bioorganic & Medicinal Chemistry Letters 14 (2004) 1049–1052
Non-peptide ꢀvꢁ3 antagonists. Part 7: 3-Substituted
tetrahydro-[1,8]naphthyridine derivatives§
Jiabing Wang,a,* Michael J. Breslin,a Paul J. Coleman,a Mark E. Duggan,a
Cecilia A. Hunt, John H. Hutchinson,a Chih-Tai Leu,b Sevgi B. Rodan,b
Gideon A. Rodan,b Le T. Duongb and George D. Hartmana
aDepartment of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA
bDepartment of Bone Biology and Osteoporosis Research, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA
Received 14 May 2003; accepted 13 November 2003
Abstract—A series of 3-substituted tetrahydro-[1,8]naphthyridine containing avb3 antagonists was prepared. A comparison of their
in vitro IC50 values to the electron properties of the 3-substituents revealed a good linear Hammett correlation (r=À1.96,
R2=0.959). Electron-withdrawing groups at the 3-position of the tetrahydro-[1,8]naphthyridine decreased potency while electron-
donating groups enhanced potency.
# 2003 Elsevier Ltd. All rights reserved.
Osteoporosis is a systemic skeletal disease characterized
by low bone mass and microarchitectural deterioration
of bone tissue, leading to increase in bone fragility and
susceptibility to fracture.2,3 Osteoporosis due to estro-
gen deficiency is caused by increase in osteoclast-medi-
ated bone resorption. It is well known that the integrin
receptor avb3, a heterodimeric cell-surface adhesion
receptor, is highly expressed in osteoclasts (bone
resorbing cells) but not in osteoblasts (bone-forming
cells).4,5 Antibodies against avb3 and the RGD-contain-
ing peptide echistatin have been shown to inhibit bone
resorption in vitro and in vivo.6À8 More recently, non-
peptide avb3 antagonists have been reported to prevent
bone loss in ovariectomized rats.9À12 These results sug-
gest that antagonists of the avb3 receptor may have
clinical utility for the prevention and treatment of
osteoporosis.
Potent non-peptide avb3 antagonists reported to date all
contain a guanidine mimetic and a carboxylic acid that
are linked together by various tethers and constraining
elements.13,14 Previously, we have reported the tetra-
hydro-[1,8]naphthyridine (THN) moiety to be a moder-
ately basic, lipophilic N-terminus that provides both
potency and selectivity for avb3.15 Compound 1, a mem-
ber of the ‘chain-shortened’ class16 of RGD mimetics,
was identified in these laboratories as a potent avb3
antagonist that displays excellent pharmacokinetics in
dogs (F=76%, t1/2=5.8 h). In this paper, we report our
efforts to further improve the potency of 1 by exploring
the effects of electron- withdrawing and electron-donating
substituents at the 3-position of the THN group.
The synthetic sequence for preparing N-methyl-b-ala-
nine 8 in high optical purity is depicted in Scheme 1.
Treatment of 5-bromo-2-methoxypyridine 2 with ethyl
acrylate under Heck coupling conditions provided 3 in
good yield. Michael addition of N-Benzyl-(R)-a-
methylbenzylamine to the acrylate 3 provided b-alanine
4 with good diastereoselectivity (de>94%).17 Selective
removal of the benzyl groups under catalytic hydro-
genation conditions furnished amine 5, which was trea-
ted with 2,4-dinitrobenzenesulfonyl chloride to afford
sulfonamide 6.18 Methylation of the amino group under
Mitsunobu conditions followed by deprotection using
mercaptoacetic acid furnished the desired N-methyl-b-
alanine 8.
§See ref 1.
* Corresponding author. Fax: +1-215-652-7310; e-mail: jiabing_wang@
merck.com
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.11.036

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J. Wang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1049–1052
The synthetic strategy used to prepare compounds 1
and 14a–e is illustrated in Scheme 2. Preparation of the
naphthyridine 10 was achieved via a Friedlander con-
densation using the aminopyridinylaldehyde 919 and
ethyl oxoheptanoate. Regioselective hydrogenation
afforded the desired tetrahydro-[1,8]naphthyridinyl
pentanoate 11 in good yield. Following saponification,
the corresponding acid was treated with EDC, HOAt
and 8 in DMF and the resulting ethyl ester was hydro-
lyzed to furnish 1. Alternatively, intermediate 11 was
functionalized at the 3-position of the THN ring and
converted to compounds 14b–e. For example, bromina-
tion of 11 in acetic acid proceeded instantaneously and
the resulting 3-bromo THN intermediate 12 converted
into 14a. On the other hand, treatment of 11 with a
mixture of concentrated H2SO4 and KNO3 provided in
good yield the desired nitro product 13, which served as
an intermediate for the preparation of 14b–e.
Synthesis of THN derivatives 14f–i, possessing a carbon-
substituent at C-3, utilized the general route outlined in
Scheme 3. Various substituents were incorporated at the
beginning of the synthesis, using the 3-bromo tetra-
hydronaphthyridine 12 as the starting material. A Suzuki
coupling with phenylboronic acid provided 12a. Simi-
larly, a Stille coupling using vinylstannane afforded the
desired vinyl-substituted intermediate 12b.20 Inter-
mediates 12c and 12d were obtained from 12 upon treat-
ment with Zn(CN)2 or MeZnCl in the presence of
palladium, respectively. All four esters (12a–d) were
converted to analogues 14f–i in three steps.
Compounds 14a–i were evaluated for their ability to
displace a non-peptide ligand from human recombinant
avb3 using a scintillation proximity bead displacement
assay (SPAV3).15 The SPAV3 IC50 values are compared
in Table 1 to the Hammett constant of para-substituents
(sp), a measure of the substituent’s ability to donate or
withdraw electrons.21 Analogues that possess electron
donating groups at the 3-position of the THN ring,
NH2 (14c), Me (14i), and vinyl (14g) increased potency
less than 2-fold. An analogue with OMe at the 3-posi-
tion would also be a good example to further examine
the electron donating effect. However, it could not be
prepared easily. Compounds with electron-withdrawing
3-substituents were less potent than 1 in the displace-
ment assay. A good correlation was observed between
potency loss and the electron withdrawing capability of
the 3-substituent. Analogues with moderate electron
withdrawing group Br (14a) decreased potency by 3-
fold. Strong electron-withdrawing groups such as CN
(14h) and NO2 (14b) decreased potency significantly,
resulting in a 24- and 52-fold potency loss, respectively.
Analogues with weak electron-withdrawing substituents
Ph (14f), NHCOCH3 (14e) and NHSO2Me (14d)
showed no significant potency changes.
Scheme 1. Preparation of N-methyl 3-(S)-(2-methoxypyrid-5-yl)-b-
alanine ethyl ester (8): (a) Pd(OAc)2, Et3N, tri-o-tolylphosphine, ethyl-
acrylate, CH3CN, 77%; (b) N-benzyl (R)-a-methylbenzyl amine/BuLi,
À78 ꢀC, then NH4Cl, 80%; (c) Pd(OH)2, H2, EtOH/EtOAc, 83%;
(d) 2,4-dinitrobenzenesulfonyl chloride, NaHCO3, 81%; (e) MeOH,
Ph3P, DEAD, 51%; (f) mercaptoacetic acid, Et3N, 78%.
Table 1. Structure–activity relationships
b
c
Compd
R
SPAV3 (IC50, nM)a Log (1/IC50
)
sp
1
H
NH2
Me
Vinyl
Ph
0.7 (2)Æ0.2
0.15
0.40
0.52
0.52
0.05
0.22
0.05
À0.36
À1.22
À1.56
0
14c
14i
14g
14f
14e
14d
14a
14h
14b
0.4
0.3 (3)Æ0.1
0.3
À0.30
À0.14
À0.08
0.05
0
0.03
0.26
0.71
0.81
0.9
0.6
0.9
2.3
16.5
36.7
NHCOCH3
NHSO2Me
Br
CN
NO2
Scheme 2. Preparation of 1 and 3-substituted THN derivatives 14a–e:
(a) CH3CO(CH2)4CO2Et, EtOH, proline, 87%; (b) Pd/C, H2, 82%; (c)
LiOH/THF/H2O, then HCl, 93%; (d) EDC, HOAt, Et3N, DMF, 1–7;
(e) LiOH/THF/H2O, then HCl; (f) Br2, acetic acid, 100%; (g) concd
H2SO4, KNO3, 10 min, 85%; (h) H2, Pd/C, EtOH; (i) MeSO2Cl, Et3N,
THF; (j) CH3COCl, Et3N, THF.
a Displacement of [125I]L-775,219 from purified human avb3 bound to
wheatgerm agglutinin scintillation proximity beads;15 data in
parentheses indicates the number of repeated assays.
b For relationship of log (1/IC50) and log (1/Ki), see ref 22 for detail.
c Hammett constants from ref 21.

J. Wang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1049–1052
1051
Scheme 3. Preparation of 3-substituted THN derivatives 14f–i; (a) C6H5B(OH)2, (Ph3P)4Pd, Na2CO3, DME, 80 ꢀC, 16 h, 71%; (b) Bu3SnCHCH2,
(Ph3P)4Pd, DMF, 120 ꢀC, 49%; (c) Zn(CN)2, (Ph3P)4Pd, DMF, 120 ꢀC; (d) MeZnCl, PdCl2(Ph3P)2, THF, 36%; (e) LiOH/THF/H2O, then HCl; (f)
EDC, HOAt, Et3N, DMF, 8; (g) LiOH/THF/H2O, then HCl.
atoms. Among the compounds studied, less than 2-fold
increase of potency was observed with electron donating
3-substituents (14i and 14g).
Acknowledgements
The authors would like to thank Audrey Wallace,
Yuan Meng, Carmen Fernandez-Metzler, Thomayant
Prueksaritanont for the pharmacokinetic studies.
Figure 1. Correlation of potency and 3-substituent effect.
References and notes
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pounds 14a–i and their electronic properties
(R2=0.959). The plot revealed a significant negative r
value of À1.96, indicating that the binding affinity is
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dog PK profile of the lead compound.
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