1490
A. Zask et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1487–1490
potent and selective TACE inhibitors. The iso-
xazolopyridine 9k had an IC50 of 6 nM against TACE
and was ꢁ300-fold selective versus MMP-1 and
ꢁ25-fold selective versus MMP-13. Importantly, in
addition to the potent TACE activity, and in contrast to
their non-butynyloxy counterparts, these compounds
were more potent in vitro in the THP cellular assay of
TNF-a release14 and in the mouse in vivo LPSinduced
TNF-a release assay14,15 (Table 4). Compound 8w was
also shown to be effective in the mouse collagen induced
arthritis model of arthritis16 at 100 mpk bid ip with a
reduction of the mean clinical score relative to control
(HulgG) comparable to EnbrelTM (etanercept) dosed at
150 ug/day (Fig. 2).
F. C.; Venkatesan, A. M.; Wehr, T.; Zask, A.; DiJoseph, J.;
Killar, L. M.; Skala, S.; Sung, A.; Sharr, M.; Roth, C.; Jin, G.;
Cowling, R.; Mohler, K. M.; Black, R. A.; March, C. J.;
Skotnicki, J. S. Bioorg. Med. Chem. Lett. 2001, 11, 2189. (c)
Levin, J. I.; Du, M. T.; DiJoseph, J. F.; Killar, L. M.; Sung,
A.; Walter, T.; Sharr, M. A.; Roth, C. E.; Moy, F. J.; Powers,
R.; Jin, G.; Cowling, R.; Skotnicki, J. S. Bioorg. Med. Chem.
Lett. 2001, 11, 235.
6. (a) Chen, J. M.; Jin, G.; Sung, A.; Levin, J. I. Bioorg. Med.
Chem. Lett. 2002, 12, 1195. (b) Levin, J. I.; Chen, J. M.; Du,
M. T.; Nelson, F. C.; Killar, L. M.; Skala, S.; Sung, A.; Jin,
G.; Cowling, R.; Barone, D.; March, C. J.; Mohler, K. M.;
Black, R. A.; Skotnicki, J. S. Bioorg. Med. Chem. Lett. 2002,
12, 1199.
7. Price, C. C.; Roberts, R. M. J. Am. Chem. Soc. 1946, 68,
1204.
8. (a) Weingarten, H.; Feder; Anal. Biochem. 1985, 147, 437.
(b) Jin, G.; Huang, X.; Black, R.; Wolfson, M.; Rauch, C.;
McGregor, H.; Ellestad, G.; Cowling, R. Anal. Biochem. 2002,
302, 269.
9. Lewis, E. J.; Bishop, J.; Bottomley, K. M. K.; Bradshaw, D.;
Brewster, M.; Broadhurst, M. J.; Brown, P. A.; Budd, J. M.;
Elliot, L.; Greenham, A. K.; Johnson, W. H.; Nixon, J. S.;
Rose, F.; Sutton, B.; Wilson, K. Br. J. Pharm. 1997, 121, 540.
10. DiJoseph, J. F.; Sharr, M. A. Drug Dev. Res. 1998, 43,
200.
In summary, bicyclic heteroaryl scaffolds have utility in
the preparation of potent and selective MMP and
TACE inhibitors. Variation of substituents on the rings
and the P10 group altered potency and selectivity of the
inhibitors through interaction with enzyme subsites.
Advanced biological evaluation of inhibitors with
appropriate P10 functionality revealed oral activity in in
vivo models of osteo and rheumatoid arthritis.
11. Bishop, J.; Greenham, A. K.; Lewis, E. J. J. Pharmacol.
Toxicol. Meth. 1993, 30, 19.
References and Notes
12. MacPherson, L. J.; Bayburt, E. K.; Capparelli, M. P.;
Carroll, B. J.; Goldstein, R.; Justice, M. R.; Zhu, L.; Hu, S-I.;
Melton, R. A.; Fryer, L.; Goldberg, R. L.; Doughty, J. R.;
Spirito, S.; Blancuzzi, V.; Wilson, D.; O’Byrne, E. M.; Ganu,
V.; Parker, D. T. J. Med. Chem. 1997, 40, 2525.
13. Maskos, K.; Fernandez-Catalan, C.; Huber, R.; Bour-
enkov, G. P.; Bartunik, H.; Ellestad, G. A.; Reddy, P.; Wolf-
son, M. F.; Rauch, C. T.; Castner, B. J.; Davis, R.; Clarke,
H. R. G.; Petersen, M.; Fitzner, J. N.; Cerretti, D.-P.; March,
C. J.; Paxton, R. J.; Black, R. A.; Bode, W. Proc. Natl. Acad.
Sci. U.S.A. 1998, 95, 3408.
1. (a) Skotnicki, J. S.; Levin, J. I.; Killar, L. M.; Zask, A. In
Metalloproteinases as Targets for Anti-Inflammatory Drugs;
Bottomley, K. M. K., Bradshaw, D., Nixon, J. S., Eds.; Bir-
khauser Verlag: Basel, 1999; pp 17–58. (b) Whittaker, M.;
Floyd, C. D.; Brown, P.; Gearing, A. J. H. Chem. Rev. 1999,
99, 2735.
2. (a) Nelson, F.; Zask, A. Exp. Opin. Invest. Drugs 1999, 8,
383. (b) Moss, M. L.; White, J. M.; Lambert, M. H.; Andrews,
R. C. Drug Disc. Today 2001, 6, 417.
3. Skotnicki, J. S.; Zask, A.; Nelson, F. C.; Albright, J. D.;
Levin, J. I. In Inhibition of Matrix Metalloproteinases Ther-
apeutic Applications; Greenwald, R. A., Zucker, S., Golub, L.
M., Eds; The New York Academy of Sciences: New York,
1999; pp 61–72.
4. Bode, W.; Fernandez-Catalan, C.; Tschesche, H.; Grams,
F.; Nagase, H.; Maskos, K. Cell. Mol. Life Sci. 1999, 55, 639.
5. (a) Levin, J. I.; Chen, J. M.; Du, M. T.; Nelson, F. C.;
Wehr, T.; DiJoseph, J. F.; Killar, L. M.; Skala, S.; Sung, A.;
Sharr, M. A.; Roth, C. E.; Jin, G.; Cowling, R.; Di, L.; Sher-
man, M.; Xu, Z. B.; March, C. J.; Mohler, K. M.; Black, R. A.;
Skotnicki, J. S. Bioorg. Med. Chem. Lett. 2001, 11, 2975. (b)
Levin, J. I.; Chen, J.; Du, M.; Hogan, M.; Kincaid, S.; Nelson,
14. Beck, G.; Bottomley, G.; Bradshaw, D.; Brewster, M.;
Broadhurst, M.; Devos, R.; Hill, C.; Johnson, W.; Kim, H.-J.;
Kirtland, S.; Kneer, J.; Lad, N.; Mackenzie, R.; Martin, R.;
Nixon, J.; Price, G.; Rodwell, A.; Rose, F.; Tang, J.-P.; Wal-
ter, D. S.; Wilson, K.; Worth, E. J. Pharmacol. Exp. Ther.
2002, 302, 390.
15. Mohler, K. M.; Sleath, P. R.; Fitzner, J. N.; Cerretti,
D.Pat; Alderson, M.; Kerwar, S. S.; Dauphine, S. T.; Otten-
Evans, C.; Greenstreet, T.; Weerawarna, K.; Kronheim, S. R.;
Petersen, M.; Gerhart, M.; Kozlosky, C. J.; March, C. J.;
Black, R. A. Nature 1994, 370, 218.
16. Trentham, D. E.; Townes, A. S.; Kang, A. H. J. Exp.
Med. 1977, 146, 857.