6154
K. Urbahns et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6151–6154
Lustig, K. WO 0035864, 2000; Chem. Abstr. 2000, 133,
43809.
5. Amato, J. S.; Karady, S.; Reamer, R. A.; Schlegel, H. B.;
Springer, J. P.; Weinstock, L. M. J. Am. Chem. Soc. 1982,
1375.
When tested for degradation by rat liver microsomes, 10
showed a clearance of 3.9 L/h kg (extrapolated from
in vitro) characterizing this molecule as a high clearance
compound.11 Further, guanidine mimetics are therefore
needed to identify biphenyl vitronectin antagonists
allowing for investigations in vivo.
6. Use of imidazolines (a) Batt, D. G.; Petraitis, J. J.;
Houghton, G. C.; Modi, D. P.; Cain, G. A.; Corjay, M.
H.; Mousa, S. A.; Bouchard, P. J.; Forsythe, M. S.;
Harlow, P. P.; Barbera, F. A.; Spitz, S. M.; Wexler, R. R.;
Jadhav, P. K. J. Med. Chem. 2000, 43, 41; (b) Pitts, W. J.;
Wityak, J.; Smallheer, J. M.; Tobin, A. E.; Jetter, J. W.;
Buynitsky, J. S.; Harlow, P. P.; Solomon, K. A.; Corjay,
M. H.; Mousa, S. A.; Wexler, R. R.; Jadhav, P. K. J. Med.
Chem. 2000, 43, 27.
7. (a) Squaric acid amides have been used as a4 integrin
inhibitors before: Head, J. C.; Porter, J. R.; McKay, C.;
WO 2002-010136; (b) Chem. Abstr. 2002, 136, 167287 and
WO 2002-042264; (c) Chem. Abstr. 2002, 136, 401746
(Celltech).
In summary, we have discovered several novel arginine
mimetics, useful for the development of aVb3 inhibitors.
To the best of our knowledge, the structural elements of
9 and 10 have not been described in the context of aVb3
inhibition hitherto.12 In particular the squaric acid
amide series showed picomolar binding affinity that
translated well into improved functional activity on
SMCs.
8. Affinity for human aVb3 in a cellular context was
determined by measuring the inhibition of the adhesion
of purified human vitronectin to HEK 293 cells transfected
with human aVb3 as described: Kumar, C. S.; James, I. E.;
Wong, A.; Mwang, V.; Field, J. A.; Nuthulaganti, P.;
Conner, J. R.; Eichman, C.; Ali, F.; Hwang, S. M.;
Rieman, D. J.; Drake, F. H.; Gowen, M. J. Biol. Chem.
1997, 272, 16390.
9. The binding constant to human serum albumin (HSA) was
determined by equilibrium dialysis (a) Loidl-Stahlhofen,
A.; Schmitt, J.; Noller, J.; Hartmann, T.; Brodowsky, H.;
Schmitt, W.; Keldenich, J. Adv. Mater. 2001, 13, 1829; (b)
Sebille, B.; Zini, R.; Madjar, C. V.; Thuaud, N.; Tillement,
J. P. J. Chromatogr. 1990, 51, 531.
10. Membrane affinities were determined as described. Briefly,
the reduction of compound concentration after incubation
with liposomal egg yolk lecithin followed by ultracentri-
fugation was measured by HPLC: Loidl-Stahlhofen, A.;
Hartmann, T.; Schottner, M.; Rohring, C.; Brodowsky,
H.; Schmitt, J.; Keldenich, J. Pharm. Res. 2001, 18, 1782.
11. The prediction of hepatic clearance was performed
according to (a) Houston, J. B.; Carlile, D. J. Drug
Metab. Rev. 1997, 29, 891; (b) Briefly, compounds were
incubated (1 lM, 37 °C) with 0.2 mg/ml rat microsomal
protein. Samples were taken at 7 time points within 30 min
to calculate half-lives and extrapolate clearance. Com-
pound A showed an extrapolated clearance of 0.6 l/h/kg in
this in vitro assay.
References and notes
1. (a) Samanen, J.; Jonak, Z.; Rieman, D.; Yue, T. L. Curr.
Pharm. Design 1997, 3, 545; (b) Miller, W. H.; Keenan, R.
M.; Willette, R. N.; Lark, M. W. Drug Discov. Today
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Opin. Ther. Pat. 2000, 10, 1367; (d) Mousa, S. A. Med.
Res. Rev. 2003, 23, 190; (e) Hoelzemann, G. Idrugs 2001,
40, 72; (f) Nagarajan, S. R.; Lu, H.-F.; Gasiecki, A. F.;
Khanna, I. K.; Parikh, M. D.; Desai, B. N.; Rogers, T. E.;
Clare, M.; Chen, B. B.; Russell, M. A.; Keene, J. L.;
Duffin, T.; Engleman, V. W.; Finn, M. B.; Freeman, S. K.;
Klover, J. A.; Nickols, G. A.; Nickols, M. A.; Shannon,
K. E.; Steininger, C. A.; Westlin, W. F.; Westlin, M. M.;
Williams, M. L. Bioorg. Med. Chem. 2007, 15, 3390; (g)
Urman, S.; Gaus, K.; Yang, Y.; Strijowski, U.; Sewald,
N.; De Pol, S.; Reiser, O. Angew. Chem. Int. Ed. 2007, 46,
3976; (h) Heckmann, D.; Meyer, A.; Marinelli, L.; Zahn,
G.; Stragies, R.; Kessler, H. Angew. Chem. Int. Ed. 2007,
46, 3571.
2. (a) Urbahns, K.; Haerter, M.; Albers, M.; Schmidt, D.;
Stelte-Ludwig, B.; Brueggemeier, U.; Vaupel, A.; Gerdes,
C. Bioorg. Med. Chem. Lett. 2002, 12, 205; The B-series
analogs of 5 and 6 are examples 25 and 26 (Table 3).
3. Urbahns, K.; Haerter, A.; Vaupel, M.; Albers, M.;
Schmidt, D.; Stelte-Ludwig, B.; Brueggemeier, U.; Gerdes,
C.; Tsujishita, H. Bioorg. Med. Chem. Lett. 2003, 13, 1071.
4. For details of the syntheses and the primary assay
procedures see: Urbahns, K.; Haerter, M.; Albers, M.;
Vaupel, A.; Schmidt, D.; Stelte-Ludwig, B.; Gerdes, C.;
12. Recent review on arginine mimetics Masic, L. P. Curr.
Med. Chem. 2006, 13, 3627.