1292
G. R. Ott et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1288–1292
Decicco, C. P.; Duan, J. J.-W. Bioorg. Med. Chem. Lett.
2007, 17, 1865.
6. Wasserman, Z. R.; Duan, J. J.-W.; Voss, M. E.; Xue,
C.-B.; Cherney, R. J.; Nelson, D. J.; Hardman, K. D.;
Decicco, C. P. Chem. Biol. 2003, 10, 215.
7. Consistent with the observed paradigm that increased
polarity drives cell potency, the dithiolane congener of 1,
though displaying equipotent activity in the enzymatic
assay and similar MMP selectivity, does not impart a
similar boost to cellular potency (WBA IC50 = 263 nM).
8. For examples of the preparation of cyclic b-amino acids
using a Curtius rearrangement, see: Bolm, C.; Schiffers, I.;
Atodiresei, I.; Hackenberger, C. P. R. Tetrahedron:
Asymmetry 2003, 14, 3455.
platforms that, in conjunction with an optimized P1’
group, have led to the discovery of potent inhibitors of
pTACE. Inhibitors 18 and 19 are active in a cellular assay
measuring suppression of LPS-induced TNF-a. These
inhibitors are selective against MMPs and displayed good
oral bioavailability in rats. Furthermore, 18 showed
excellent oral bioavailability in beagle dogs. In a rodent
model of endotoxemia, 18 displayed an oral ED50 of 1–
3 mg/kg in the suppression of TNF-a.
Acknowledgment
9. All new compounds were consistent with 1H NMR and
low resolution mass spectrometry data.
10. The numbering system of the oxaspiro[4.4]nonane system
is reflected in the structure.
11. The GOESY is a double-PFG-spin-echo, transient nOe
experiment using shape selective pulses and pulse field
gradients in which the results appear similar to a steady-
state nOe difference experiment. Since excitation is done
with shaped pulses, a much narrower region of the
spectrum is affected so it is possible to see weaker nOes
than with a steady-state nOe difference experiment, see
Stott, K.; Keeler, J.; Van, Q. N.; Shaka, A. J. J. Magn.
Reson. 1997, 125, 302.
We thank John Giannaras, Sherrill Nurnberg, and Paul
Strzemienski for running in vitro assays, Robert J. Col-
lins for LPS study in animals, Bernice Brogdon, Bing
Lu, Hang Zheng, and Jingtao Wu for assistance in phar-
macokinetic studies, Maria Ribadeneira for Caco-2
assay, and Gerry Everlof for running stability screens.
We also thank Mary Malley for help in the preparation
of Fig. 4.
References and notes
12. The coordinates for 21 have been placed in the Cambridge
Crystallographic Data Centre, deposition number: CCDC
670062.
1. Newton, R. C.; Decicco, C. P. J. Med. Chem. 1999, 42,
2295.
2. (a) Moreland, L. W.; Baumgartner, S. W.; Schiff, M. H.;
Tindall, E. A.; Fleischmann, R. M.; Weaver, A. L.;
Ettlinger, R. E.; Cohen, S.; Koopman, W. J.; Mohler, K.;
Widmer, M. B.; Blosch, C. M. N. Engl. J. Med. 1997, 337,
141; (b) Lipsky, P. E.; van der Heijde, D. M. F. M. E.; St.
Clair, W.; Furst, D. E.; Breedveld, F. C.; Kalden, J. R.;
Smolen, J. S.; Weisman, M.; Emery, P.; Feldmann, M.;
Harriman, G. R.; Maini, R. N. N. Engl. J. Med. 2000, 343,
1594; (c) Machold, K. P.; Smolen, J. S. Exp. Opin. Bio.
Ther. 2003, 3, 351.
13. Details of the pTACE (porcine TACE), MMPs, human
whole blood assay (WBA) as well as LPS-mouse efficacy
model are reported in previous publication, see: Xue,
C.-B.; Voss, M. E.; Nelson, D. J.; Duan, J. J.-W.;
Cherney, R. J.; Jacobson, I. C.; He, X.; Roderick, J.;
Chen, L.; Corbett, R. L.; Wang, L.; Meyer, D. T.;
Kennedy, K.; DeGrado, W. F.; Hardman, K. D.;
Teleha, C. A.; Jaffee, B. D.; Liu, R.-Q.; Copeland, R.
A.; Covington, M. B.; Christ, D. D.; Trzaskos, J. M.;
Newton, R. C.; Magolda, R. L.; Wexler, R. R.; Decicco,
C. P. J. Med. Chem 2001, 44, 2636.
3. For a recent review, see: Skotnicki, J. S.; Levin, J. I. Ann.
Rep. Med. Chem. 2003, 38, 153.
14. (a) Schlondorff, J.; Becherer, J. D.; Blobel, C. P. Biochem.
J. 2000, 347, 131; (b) Solomon, K. A.; Covington, M. B.;
Decicco, C. P.; Newton, R. C. J. Immunol. 1997, 159,
4524.
15. Wu, J.-T.; Zeng, H.; Qian, M.; Brogdon, B. L.; Unger, S.
E. Anal. Chem. 2000, 72, 61.
16. For related analogs in the a,b-cyclic-b-benzamido
hydroxamic acid series, replacement of the 4-[(2-methyl-
quinolin-4-yl)methoxy]benzamide P1’ substituent with 4-
[(2,6-dimethylpyridin-4-yl)methoxy]benzamide resulted in
maintenance of pTACE activity but loss in both WBA
activity and selectivity against MMPs-2 and -13. Ott, G.
R.; Asakawa, N, unpublished results.
4. Duan, J. J.-W.; Chen, L.; Lu, Z.; Xue, C.-B.; Liu,
R.-Q.; Covington, M. B.; Qian, M.; Wasserman, Z.
R.; Vaddi, K.; Christ, D. D.; Trzaskos, J. M.;
Newton, R. C.; Decicco, C. P. Bioorg. Med. Chem.
Lett. 2008, 18, 241.
5. (a) Ott, G. R.; Asakawa, N.; Lu, Z.; Liu, R.-Q.; Covington,
M. B.; Vaddi, K.; Qian, M.; Newton, R. C.; Traskos, J. M.;
Christ, D. D.; Decicco, C. P.; Duan, J. J.-W. Bioorg. Med.
Chem. Lett. 2008, 18, 694; (b) Chen, X.-T.; Ghavimi, B.;
Corbett, R. L.; Xue, C.-B.; Liu, R.-Q.; Covington, M. B.;
Qian, M.; Vaddi, K. G.; Christ, D. D.; Hartman, K. D.;
Ribadeneira, M. D.; Trzaskos, J. M.; Newton, R. C.;