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R. D. Mazzola et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5809–5814
5. (a) Bathon, J. M.; Martin, R. W.; Fleischmann, R. M.; Tesser, J. R.; Schiff, M. H.;
with a MMP-7 Ki of about 4 lM. Furthermore, as the amide became
Keystone, E. C.; Genovese, M. C.; Wasko, M. C.; Moreland, L. W.; Weaver, A. L.;
Markenson, J.; Finck, B. K. N. Engl. J. Med. 2000, 343, 1586; (b) Moreland, L. W.;
Baumgartner, S. W.; Schiff, M. H.; Tindal, 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.
larger as in prolinol derivative 34 or when the amide was replaced
with a cyano 39, the selectivity was enhanced providing com-
pounds with selectivity ratios of greater than 3000 versus all the
MMPs and ADAMs we examined.
Despite the exceptional potency and selectivity profiles, many
of these analogs displayed diminished activity in the human whole
blood assay (HWB) and poor pharmacokinetic properties. For com-
6. For a recent review of TACE inhibitors, see Skotnicki, J. S.; Levin, J. I. Ann. Rep.
Med. Chem. 2003, 38, 153.
7. (a) Newton, R. C.; Solomon, K. A.; Covington, M. B.; Decicco, C. P.; Haley, P. J.;
Friedman, S. M.; Vaddi, K. Ann. Rheum. Dis. 2001, 60, 25; (b) Moss, M. L.; White,
J. M.; Lambert, M. H.; Andrews, R. C. Drug Discov. Today 2001, 6, 417.
8. (a) Lukacova, V.; Zhang, Y.; Kroll, D. M.; Raha, S.; Comez, D.; Balaz, S. J. Med.
Chem. 2005, 48, 2361; (b) Maskos, K.; Fernandez-Catalan, C.; Huber, R.;
Bourenkov, G.; Bartunik, H.; Ellestad, G.; Reddy, P.; Wolfson, M.; Rauch, C.;
Castner, B.; Davis, R.; Clark, H.; Petersen, M.; Fitzner, J.; Cerratti, D.; March, C.;
Paxton, R.; Black, R.; Bode, W. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 3408; (c)
Rush, T. S., III; Powers, R. Curr. Top. Med. Chem. 2004, 4, 1311.
9. Renkiewicz, R.; Qiu, L.; Lesch, C.; Un, X.; Devalaraja, R.; Cody, T.; Kaldjian, E.;
Welgus, H.; Baragi, V. Arthritis Rheum. 2003, 48, 1742.
10. Duan, J. J.-W.; Chen, L.; Wasserman, Z. R.; Zhonghui, L.; Rui-Qin, L.; Covington,
M. B.; Qian, M.; Hardman, K. D.; Magolda, R. L.; Newton, R. C.; Christ, D. D.;
Wexler, R. R.; Decicco, C. P. J. Med. Chem. 2002, 45, 4954.
pounds 13–39, HWB IC50’s were found to be 2 lM or larger. Fur-
thermore, compounds like 26 failed to display detectable plasma
levels in a rat PK study,19 which was characteristic for most of
these amides. The low oral availability observed for 26 may, in
part, be attributed to poor absorption as was suggested in a
Caco-2 assay ((AP to BL) = 3 nm/s). In contrast, compound 39 dis-
played a reasonable AUC (>2500 nM h, 10 mpk, po) and stood out
as having the best PK profile.
In summary, we have explored the effect of S30 and hydrogen
bond acceptor variations on potency and selectivity of a series of
cyclopropyl hydroxamic acids. Many of these inhibitors displayed
potent TACE Ki’s in the picomolar range while maintaining good
and sometimes excellent selectivity over MMP-1, MMP-2, MMP-
3, MMP-7, MMP-14, and ADAM-10. More importantly, 39 dis-
played a good PK profile while maintaining a good in vitro profile.
11. (a) Levin, J. I.; Chen, J. M.; Laakso, L. M.; Du, M.; Schmid, J.; Xu, W.; Cummons,
T.; Xu, J.; Jin, G.; Barone, D.; Skotnicki, J. S. Bioorg. Med. Chem. Lett. 2006, 16,
1605; (b) Levin, J. I.; Chen, J. M.; Laakso, L. M.; Du, M.; Du, X.; Venkatesan, A. M.;
Sandanyaka, V.; Zask, A.; Xu, J.; Xu, W.; Zhang, Y.; Skotnicki, J. S. Bioorg. Med.
Chem. Lett. 2005, 15, 4345.
12. Zhu, Z.; Mazzola, R.; Sinning, L.; McKittrick, B.; Niu, X.; Lundell, D.; Sun, J.; Orth,
P.; Guo, Z.; Madison, V. J. Med. Chem. 2008, 51, 725.
13. Huang, A.; Joseph-McCarthy, D.; Lovering, F.; Sun, L.; Wang, W.; Xu, W.; Zhu,
Y.; Cui, J.; Zhang, Y.; Levin, J. I. Bioorg. Med. Chem. 2007, 15, 6170.
14. All new compounds gave satisfactory 1H NMR and MS in accord with their
assigned structure. All final targets showed LCMS purities >95%.
15. Majid, T. N.; Knochel, P. Tetrahedron Lett. 1990, 31, 4413.
Acknowledgments
16. Von der Saal, W.; Reinhardt, R.; Seidenspinner, H.-M.; Satwitz, J.; Quast, H.
Liebigs Ann. Chem. 1989, 703.
17. N-(2,4-Dimethoxybenzyl)-O-(4-methoxybenzyl) hydroxylamine was prepared
by the following scheme:
We wish to thank Drs. Johnathan Piwinski, William Greenlee,
and Michael Czarniecki for their continued support of the project.
Also, we thank Emily Luk for the LC–MS analysis and Dr. T.M. Chan
and Rebecca Osterman for help with NMR structural
determinations.
O
O
Cl
OH
N
References and notes
O
O
a
b
+
1. (a) Killar, L.; White, J.; Black, R.; Peschon, J. J. Ann. NY Acad. Sci. 1999, 878, 442;
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O
O
N
HN
O
O
O
O
O
Reagents and conditions: (a) 1—DIPEA, CH3CN, reflux, 3 h; 2—20%
NH2NH2ꢁH2O, CH3OH, reflux, 20 min; 3—2,4-dimethyoxybenzaldehyde,
NaOAc, CH3CO2H/CH3OH, reflux, 2 h, 50% (over
CH3CO2H, 86%.
3 steps); (b) Na(CN)BH3,
18. For details concerning all in vitro assay conditions used herein, please see Ref. 12.
19. For experimental details of the pharmacokinetic assay, see: Korfmacher, W. A.;
Cox, K. A.; Ng, K. J.; Veals, J.; Hsieh, Y.; Weinhaus, S.; Broske, L.; Prelusky, D.;
Nomeir, A.; White, R. E. Rapid Commun. Mass Spectrum 2001, 15, 335.
4. Lipsky, P. E.; van der Heijde, D. M.; St. Clair, E. W.; Furst, D. E.; Breedveld, F. C.;
Kalden, J. R.; Smolen, J. S.; Weisman, M.; Emery, P.; Feldman, M.; Harriman, G.
R.; Maini, R. N. N. Engl. J. Med. 1997, 343, 1594.