J. J.-W. Duan et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2035–2040
2039
approximately 300-fold selective over MMP-2 and -9.
Lactam 2o also had good permeability in Caco-2 assay
(Papp=11ꢀ10ꢁ6 cm/s), indicating that it may have good
oral absorption in vivo. The high affinity obtained with
most of the R1 analogues further validated the compu-
ter model shown in Figure 2.
binding measurement of 2g, and Maria Ribadeneira for
Caco-2 study of 2o.
References and Notes
1. (a) Aggarwal, B. B.; Kohr, W. J.; Hass, P. E.; Moffat, B.;
Spencer, S. A.; Henzel, W. J.; Bringman, T. S.; Nedwin, G. E.;
Goeddel, D. V.; Harkins, R. N. J. Biol. Chem. 1985, 260, 2345.
(b) Aggarwal, B. B.; Natarajan, K. Eur. Cytokine Network
1996, 7, 93.
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. Eng. 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. Eng. J. Med. 2000, 343, 1594.
In an attempt to further improve cellular potency, an
amino group was introduced to the 3-position of the
pyrrolidinone (R3). Unfunctionalized amino group
yielded potent and selective TACE inhibitors (2p–r,
racemic mixture) regardless whether R1 is present
(methyl and n-propyl) or not. Unfortunately, none of
them improved WBA potency, with 2q the most pro-
mising at 1.1 mM. Dimethylamino R3 analogue (2s) is
6-fold less potent for pTACE than the amino com-
pound 2q. Similar to the SAR trend observed with R3
being hydrogen, inversion of stereocenter at the
a-position of the hydroxamate resulted in 100-fold loss
of potency (2t vs 2r).
3. Newton, R. C.; Decicco, C. P. J. Med. Chem. 1999, 42,
2295.
4. (a) Black, R. A.; Rauch, C. T.; Kozlosky, C. J.; Peschon,
J. J.; Slack, J. L.; Wolfson, M. F.; Castner, B. J.; Stocking,
K. L.; Reddy, P.; Srinivasan, S.; Nelson, N.; Bolani, N.;
Schooley, K. A.; Gerhart, M.; Devis, R.; Fitzner, J. N.; John-
son, R. S.; Paxton, R. J.; March, C. J.; Cerretti, D. P. Nature
1997, 385, 729. (b) Moss, M. L.; Jin, S.-L. C.; Milla, M. E.;
Burkhart, W.; Carter, H. L.; Chen, W.-J.; Clay, W. C.; Dids-
bury, J. R.; Hassler, D.; Hoffman, C. R.; Kost, T. A.; Lam-
bert, M. H.; Leesnitzer, M. A.; McCauley, P.; McGeehan, G.;
Mitchell, J.; Moyer, M.; Pahel, G.; Rocque, W.; Overton,
L. K.; Schoenen, F.; Seaton, T.; Su, J.-L.; Warner, J.; Willard,
D.; Becherer, J. D. Nature 1997, 385, 733.
N-Hydroxyformamide (retrohydroxamate) group has
been reported to be an effective zinc-binding group to
replace the commonly used hydroxamte group in MMP
and TACE inhibitors.9a,16 Hence, N-hydroxyformamide
analogue 24 was prepared and tested. Indeed, it was
highly potent for pTACE (2 nM) and exhibited excellent
selectivity relative to the three MMPs (at least
1000-fold). However, it did not offer any advantages
over the conventional hydroxamate in the WBA and
was approximately 5-fold less potent than 2b.
5. Carter, P. H.; Scherle, P. A.; Muckelbauer, J. A.; Voss,
M. E.; Liu, R.-Q.; Thompson, L. A.; Tebben, A. J.; Solomon,
K. A.; Lo, Y. C.; Li, Z.; Strzemienski, P.; Yang, G.; Fala-
hatpisheh, N.; Xu, M.; Wu, Z.; Farrow, N. A.; Ramnarayan,
K.; Wang, J.; Rideout, D.; Yalamoori, V.; Domaille, P.;
Underwood, D. J.; Trzaskos, J. M.; Friedman, S. M.; Newton,
R. C.; Decicco, C. P. Proc. Natl. Acad. Sci. U.S.A. 2001, 98,
11879 and references therein.
Two analogues (25 and 26) with (2,6-dimethylpyr-
idinyl)methoxy group in place of the (2-methyl-4-qui-
nolinyl)methoxy P10 group were evaluated. In both
cases, significant loss of enzyme and cell activity was
observed (25 vs 2f, 26 vs 2o). For the N-hydroxy-
formamide-derived inhibitor, an analogue with benzy-
loxy P10 group (27) also had diminished TACE affinity
(50-fold) compared to 24. These data demonstrated that
the (2-methyl-4-quinolinyl)methoxy group remained a
superior P10 group for this new series of lactam TACE
inhibitors.
6. Nelson, F. C.; Zask, A. Exp. Opin. Invest. Drugs 1999, 8,
383.
7. Wojtowicz-Praga, S.; Torri, J.; Johnson, M.; Steen, V.; Mar-
shall, J.; Ness, E.; Dickson, R.; Sale, M.; Rasmussen, H. S.;
Chiodo, T. A.; Hawkins, M. J. J. Clin. Oncol. 1998, 16, 2150.
8. (a) For selective TACE inhibitors reported from our group:
Duan, J. J.-W.; Chen, L.; Wasserman, Z. R.; Lu, Z.; Liu, R.-
Q.; 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. (b) Xue, C.-B.; Voss,
M. E.; Nelson, D. J.; Duan, J. J.-W.; Cherney, R. J.; Jacob-
son, 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.; Dec-
icco, C. P. J. Med. Chem. 2001, 44, 2636. (c) Xue, C.-B.; He,
X.; Corbett, R. L.; Roderick, J.; Wasserman, Z. R.; Liu, R.-
Q.; Jaffee, B. D.; Covington, M. B.; Qian, M.; Trzaskos, J. M.;
Newton, R. C.; Magolda, R. L.; Wexler, R. R.; Decicco, C. P.
J. Med. Chem. 2001, 44, 3351.
In summary, new TACE inhibitors were discovered
using an N-hydroxy-2-(2-oxo-3-pyrrolidinyl)acetamide
scaffold (2). Incorporation of the TACE selective
(2-methyl-4-quinolinyl)methoxy P10 group produced a
series of highly potent inhibitors of TACE that are
selective relative to MMP-1,-2, and -9. Many com-
pounds were also active in the cellular assay (WBA),
with 2o being most potent with an IC50 of 0.42 mM. The
discovery of this series added diversity to our TACE
inhibitor portfolio and can potentially offer new oppor-
tunity to develop TACE inhibitors for the treatment of
rheumatoid arthritis.
9. (a) For selective TACE inhibitors from other groups:
Rabinowitz, M. H.; Andrews, R. C.; Becherer, J. D.; Bickett,
D. M.; Bubacz, D. G.; Conway, J. G.; Cowan, D. J.; Gaul,
M.; Glennon, K.; Lambert, M. H.; Leesnitzer, M. A.;
McDougald, D. L.; Moss, M. L.; Musso, D. L.; Rizzolio,
M. C. J. Med. Chem. 2001, 44, 4252. (b) Holms, J.; Mast, K.;
Acknowledgements
We thank John Giannaras, Sherrill Nurnberg and Paul
Strzemienski for assistance in enzymatic and cell assays,
Mingxin Qian and David D. Christ for human protein