4836 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 20
Coleman et al.
described for 24 (78% yield). 1H NMR (400 MHz, CDCl3): δ
10.1 (s, 1H), 9.07 (s, 2H), 3.31 (m, 1H), 1.35 (d, J ) 6.8 Hz,
6H).
and the distal femoral metaphysis (DFM, 12-25% of the
distance from distal to proximal end) was conducted. Signifi-
cant bone loss occurred after ovariectomy (P < 0.01).
3-Ar yl-9-(5,6,7,8-t et r a h yd r o-[1,8]n a p h t h yr id in -2-yl)-
n on a n oic Acid s 5a , 4a , 5b, 5c, 5d , 5f, 5g, a n d 5h P r ep a r ed
Accor d in g to th e Meth od s Descr ibed for 5e. 3-(R, S)-(3-
F lu or op h en yl)-9-(5,6,7,8-tetr a h yd r o-[1,8]n a p h th yr id in -2-
yl)-n on a n oic Acid (5a ). 3-fluorobenzaldehyde was trans-
Ack n ow led gm en t. We thank the analytical depart-
ment for LogP and protein binding determinations and
Robert Lynch, Audrey Wallace, and Yuan Meng for their
help with the studies described herein. We also thank
Dr. Michael Patane for the synthetic studies related to
compound 15 and Carl Homnick for developing chiral
HPLC conditions.
1
formed to acid 5a per Scheme 1. H NMR (300 MHz, CDCl3):
δ 9.83 (br s, 1H), 7.24 (m, 2H), 6.88 (m, 3H), 6.28 (m, 1H),
3.42 (m, 2H), 3.05 (m, 1H), 2.70 (m, 6H), 1.88 (m, 2H), 1.59
(m, 4H), 1.19 (m, 7H).
3-(R, S)-(3-F lu or op h en yl)-9-(5,6,7,8-t et r a h yd r o-[1,8]-
n a p h th yr id in -2-yl)-n on -4-en oic Acid (4a ). 3-Fluorobenzal-
dehyde was transformed to acid 4a per Scheme 1. 1H NMR
(300 MHz, CDCl3): δ 8.18 (br s, 1H), 7.31 (m, 1H), 6.92 (m,
1H), 6.88 (m, 2H), 6.38 (m, 1H), 5.55 (m, 2H), 3.81 (m, 1H),
3.51 (m, 2H), 2.71 (m, 6 H), 2.18 (m 1H), 1.95 (m, 3H), 1.77
(m, 1H), 1.51 (m, 3H).
Refer en ces
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Today 2001, 37, 703-722.
(2) (a) Ershler, W. B. New Concepts in the Pathogenesis and
Treatment of Osteoporosis. Front. Biomed. 2000, 1, 41-51. (b)
Eastell, R. Treatment of Postmenopausal Osteoporosis. N. Engl.
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1998, 3, d757-d768.
(4) For reviews see (a) Coleman, P. J .; Duong, L. T. Ligands to the
Integrin Receptor Rvâ3. Expert. Opin. Ther. Pat. 2002, 12, 1009-
1021. (b) Miller, W. H.; Keenan, R. M.; Willette, R. N.; Lark, M.
W. Identification and In Vivo Efficacy of Small-Molecule An-
tagonists of Integrin Rvâ3 (the Vitronectin Receptor) Drug
Discovery Today 2000, 5, 397-408. (c) Hartman, G. D.; Duggan,
M. E. Rvâ3 Integrin Antagonists as Inhibitors of Bone Resorption.
Expert. Opin. Invest. Drugs 2000, 9, 1281-1291.
(5) Fisher, J . E.; Caulfield, M. P.; Sato, M.; Quartuccio, H. A.; Gould,
R. J .; Garsky, V. M.; Rodan, G. A.; Rosenblatt, M. Inhibition of
Osteoclastic Bone Resorption in Vivo by Echistatin, an “Arginyl-
Glycyl-Aspartyl” (RGD)-Containing Protein. Endocrinology 1993,
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(6) Yamamoto, M.; Fisher, J . E.; Gentile, M.; Seedor, J . G.; Leu,
C.-T.; Rodan, S. B.; Rodan, G. A. The Integrin Ligand Echistatin
Prevents Bone Loss in Ovariectomized Mice and Rats. Endocri-
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(7) Crippes, B. A.; Engleman, V. W.; Settle, S. L.; Delarco, J .;
Ornberg, R. L.; Helfrich, M. H.; Horton, M. A.; Nickols, G. A.
Antibody to â3 Integrin Inhibits Osteoclast-Mediated Bone
Resorption in the Thyroparathyroidectomized Rat. Endocrinol-
ogy 1996, 137, 918.
3-(S)-(2,3-Dih yd r o-ben zofu r a n -6-yl)-9-(5,6,7,8-tetr a h y-
d r o-[1,8]n a p h th yr id in -2-yl)-n on a n oic Acid (5b). Aldehyde
17 was transformed to acid 5b per Scheme 1. 1H NMR (300
MHz, CDCl3): δ 7.3 (m, 1H); 7.11 (m, 1H); 6.8 (m, 1H), 6.62
(s, 1H), 6.35 (m, 1H), 4.5 (m, 2H), 3.51 (m, 2H), 3.15 (m, 3H),
2.61 (m, 5H), 1.91 (m, 3H), 1,72 (m, 4H), 1.4 (m, 6H).
3-(S)-(6-Meth oxypyr idin -3-yl)-9-(5,6,7,8-tetr ah ydr o-[1,8]-
n a p h th yr id in -2-yl)-n on a n oic Acid (5c). 6-Methoxypyridine-
3-carboxaldehyde (19) was transformed to acid 5c per Scheme
1
1. H NMR (300 MHz, CD3OD): δ 8.31 (m, 1H), 8.19 (s, 1H),
7.59 (m, 1H), 7.45 (m, 1H), 6.60(m, 1H), 4.16 (s, 3H), 3.51 (m,
2H), 3.20 (m, 1H), 2.79 (m, 6H), 1.95 (m, 2H), 1.71 (m, 4H),
1.37 (m, 3H).
3-(S)-(Qu in olin -3-yl)-9-(5,6,7,8-t et r a h yd r o-[1,8]n a p h -
th yr id in -2-yl)-n on a n oic Acid (5d ). The 3-quinoline carbox-
1
aldehyde was transformed to acid 5d per Scheme 1. H NMR
(300 MHz, CDCl3): δ 10.2 (br s, 1H), 8.92 (d, J ) 1.8 Hz, 1H),
8.15 (d, J ) 8.5 Hz, 1H), 7.96 (d, J ) 1.8 Hz, 1H), 7.82 (d, J )
7.5 Hz, 1H), 7.71 (t, J ) 7.5 Hz, 1H), 7.54 (t, J ) 7.5 Hz, 1H),
7.05 (d, J ) 7.3 Hz, 1H), 6.25 (d, J ) 7.3 Hz, 1H), 5.6 (m, 1H),
3.56 (m, 1H), 3.40 (m, 2H), 2.75 (m, 2H), 2.65 (m, 2H), 2.58
(m, 2H), 2.01 (m, 2H), 1.91 (m, 2H), 1.65 (m, 2H), 1.45 (m,
2H).
3-(S)-(Meth ylp yr im id in -5-yl)-9-(5,6,7,8-tetr a h yd r o-[1,8]-
n a p h th yr id in -2-yl)-n on a n oic Acid (5f). Aldehyde 24 was
transformed to acid 5f per Scheme 1. HPLC RT ) 9.20 min
(Vydac C18; 95/5 to 5/95 H2O/MeCN gradient over 15 min).
1H NMR (400 MHz, MeOD): δ 8.54 (s, 2H), 7.36 (d, J ) 7.2
Hz, 1H), 6.43 (d, J ) 7.2 Hz, 1H), 3.39 (t, J ) 8.0 Hz, 2H),
3.27 (s, 3H), 3.12 (m, 1H), 2.72 (t, J ) 6.0 Hz, 2H), 2.58 (m,
4H), 1.87 (m, 2H), 1.76 (m, 1H), 1.61 (m, 3H), 1.41 (m, 1H),
1.29 (m, 5H).
3-(S)-(2-Meth oxyp yr im id in -5-yl)-9-(5,6,7,8-tetr a h yd r o-
[1,8]n a p h th yr id in -2-yl)-Non a n oic Acid (5g). Aldehyde 25
was transformed to acid 5g per Scheme 1. 1H NMR (500 MHz,
CDCl3): δ 8.40 (s, 2H), 7.25 (d, J ) 7.5 Hz, 1H), 6.28 (d, J )
7.5 Hz, 1H), 4.00 (s, 3H), 3.47 (m, 2H), 3.25 (m, 1H), 2.72 (m,
3H), 2.56 (m, 3H), 1.92 (m, 2H), 1.83 (m, 1H), 1.68 (m, 2H),
1.59 (m, 2H), 1.29 (m, 5H).
3-(S)-(2-Isop r op ylp yr im id in -5-yl)-9-(5,6,7,8-tetr a h yd r o-
[1,8]n a p h th yr id in -2-yl)-n on a n oic Acid (5h ). The aldehyde
26 was transformed to acid 5h per Scheme 1. 1H NMR (400
MHz, CDCl3): δ 8.60 (s, 2H), 7.39 (d, J ) 7.3 Hz, 1H), 6.48 (d,
J ) 7.3 Hz, 1H), 3.43 (m, 2H), 3.16 (m, 2H), 2.76 (m, 2H), 2.60
(m, 3H), 2.53 (m, 1H), 1.91 (m, 2H), 1.79 (m, 1H), 1.63 (m,
3H), 1.47 (m, 1H), 1.30 (m, 1H).
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Griggs, D. W.; Settle, S. L.; Ruminski, P. G.; Teitelbaum, S. L.
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D. J .; Drake, F. H.; Bradbeer, J . N.; Mathur, A.; Erhard, K. F.;
Newlander, K. A.; Ross, S. T.; Salyers, K. L.; Smith, B. R.; Miller,
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tor Antagonist SB 265123 for Prevention of Bone Loss in
Osteoporosis. J . Pharmacol. Exp. Ther. 1999, 291, 612-617.
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E.; Callahan, J . F.; Calvo, R. R.; Cousins, R. D.; Erhard, K. F.;
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Venslavsky, J . W.; Yuan, C. C.-K.; Haltiwanger, R. C.; Gowen,
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Stroup, G. B.; Azzarano, L. M.; Salyers, K. L.; Smith, B. R.;
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Receptor Antagonist. J . Pharm. Exp. Ther. 2002, 302, 205.
(12) Hutchinson, J . H.; Halczenko, W.; Brashear, K. M.; Breslin, M.
J .; Coleman, P. J .; Duong, L. T.; Fernandez-Metzler, C.; Gentile,
M. A.; Fisher, J . E.; Hartman, G. D.; Huff, J . R.; Kimmel, D. B.;
Leu, C.-T.; Meissner, R. S.; Merkle, K.; Nagy, R.; Pennypacker,
B.; Perkins, J . J .; Prueksaritanont, T.; Rodan, G. A.; Varga, S.
L.; Wesolowski, G. A.; Zartman, A. E.: Rodan, S. B.; Duggan,
M. E. Nonpeptide Rvâ3 Antagonists. 8. In Vitro and in Vivo
Evaluation of a Potent Rvâ3 Antagonist for the Prevention and
Treatment of Osteoporosis. J . Med. Chem. 2003, 46, 4790-4798.
Ova r iectom ized Ra t Mod el. Female Sprague-Dawley
rats aged 7 months (body weight 325 g) were used. They were
ovariectomized (OVX) by a dorsal approach and then started
on treatment the next day with either 5e or 5f. Treatment
continued for 28 (5f experiment) or 42 days (5e experiment).
At necropsy, right femurs were collected and placed in 70%
ethanol. They were defleshed and analyzed (bone mineral
density, BMD) by dual-energy X-ray absorptiometry (DXA).
BMD of the central femur (CF), the distal 25% of the femur,