T. E. Barta et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2815±2817
2817
Therapeutic Applications; Greenwald, R. A., Zucker, S.,
Golub, L. M., Eds.; The New York Academy of Sciences: NY,
1999; pp 583±586.
3. The hypothesis that sparing MMP-1 is necessary and su-
cient to prevent the musculoskeletal stiening has been called
into question in view of recent clinical results where it is
observed that certain inhibitors that inhibit MMP-1 never-
theless do not appear to show the side eect. See Shaw, T.;
Nixon, J. S.; Bottomley, K. M. Exp. Opin. Invest. Drugs 2000,
9, 1469.
4. Shalinsky, D. R.; Brekken, J.; Zou, H.; McDermott, C. D.;
Forsyth, P.; Edwards, D.; Margosiak, S.; Bender, S.; Truitt,
G.; Wood, A.; Varki, N. M.; Appelt, K. In Inhibition of
Matrix Metalloproteinases: Therapeutic Applications; Green-
wald, R. A., Zucker, S., Golub, L. M., Eds.; The New York
Academy of Sciences: NY, 1999; pp 236±270.
5. Lovejoy, B.; Welch, A. R.; Carr, S.; Luong, C.; Broka, C.;
Hendricks, R. T.; Campbell, J. A.; Walker, A. M.; Martin, R.;
Van Wart, H.; Browner, M. F. Nat. Struct. Biol. 1999, 6, 217.
6. Nagasawa, H. T.; Kawle, S. P.; Elberling, J. A.; DeMaster,
E. G.; Fukoto, J. M. J. Med. Chem. 1995, 38, 1865.
7. Sulfonyl chloride 2 is available from Lancaster, but in our
hands reactions involving the ethyl ester seemed cleaner.
8. (a) Analogue 7h was prepared by ortholithiation of the
corresponding 3-¯uorosulfonamide, followed by a carbon
dioxide quench. The acid was transformed to the hydroxamate
by making the acid chloride and reacting with tetra-
hydropyranhydroxylamine. Full details will be reported in a
subsequent communication. (b) Sindelar, K.; Hrubantova, M.;
Svatek, E.; Matousova, O.; Metysova, J. Collect. Czech.
Chem. Commun. 1989, 54, 2240
Figure 2. X-ray crystal structure of 7h bound to hMMP-8.
potency across the board. Perhaps any van der Waals
stabilization of P10 from the pocket is minimal for these
analogues. The most active analogues (6h±i, and 7h)
have P10 subunits which reach down to the bottom of
the pocket, having a length and volume similar to what
is seen in, for example, Ag-3340 and RS-130630.
The potency of 6h and 6i towards the target enzymes
and the extraordinary level of selectivity against MMP-1
has encouraged us to pursue this aryl series further.
9. Compound 7h had an IC50 of 33 nM against this enzyme.
10. Assays were conducted at six dilutions with an N at least
equal to 2. Inhibitors were tested against puri®ed hMMP-13,
hMMP-1 and hMMP-2 using an enzyme assay based on clea-
vage of the ¯uorogenic peptide MCA-Pro-Leu-Gly-Leu-Dpa-
Ala-Arg-NH2. This is similar to conditions described by
Knight, C. G.; Willenbrock, F.; Murphy, G. in FEBS Lett.
1992, 296, 263, except that 0.02% ®nal concentration of 2-
mercaptoethanol was used in the MMP-13 and MMP-1
assays.
Additional results will be reported in due course.11
References and Notes
1. Steward, W. P. Cancer Chemother. Pharmacol. 1999, 43,
S56±S60.
2. Yocum, S. A.; Lopresti-Morrow, L. L.; Reeves, L. M.;
Mitchell, P. G. In Inhibition of Matrix Metalloproteinases:
11. Barta, T. E.; Becker, D. P.; Bedell, L. J.; Freskos, J. N.;
McDonald, J. J.; Mischke, B. V.; Rao, S. N. WO 9838859,
1998; Chem. Abstr. 1998, 129, 260344.