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depth of the MMP-13 S10 pocket, which is distinct from other
MMP family members such as MMP-1 and MMP-2, which have
shallower pockets. The hydroxamate chelates zinc at two positions
and makes a hydrogen bond to Glu223. One of the sulfone oxygens
interacts with the protein backbone. The tetrazole group forms a
single direct hydrogen bond to the peptide at Thr245 (3.0 Å); the
remainder of the side chain interactions with the protein are van
der Waals contacts. The S10 pocket of MMP-13 is presumably able
to flex to accommodate inhibitors of various sizes and shapes, such
as the isomeric aryl heterocycles 4e, 4i, and 4j. This crystal struc-
ture adds to the body of structural knowledge within this impor-
tant class of proteinases.
We achieved the primary goal of this project, to improve on the
0.59 h half-life we measured for the lead amide compound 3. We
see in Table 1 heterocyclic compounds with half-lives ranging from
1.4 to 4.8 h; compounds having good BA (e.g., tetrazole 4c, 26%;
and oxadiazole 4f, 28%); and analogs with encouraging Cmax values.
Based on our data, we believe selected heterocyclic analogs in this
Letter will be promising drug candidates for the treatment of
arthritis, cancer, and post-MI left ventricular hypertrophy (CHF),
as we will report in due course.
Figure 2. Structure of MMp-13 with compound 4c bound at the catalytic site. The
inhibitor binds deeply within the S10 pocket of the active site and causes
a
Supplementary data
conformational change opening the loop to accommodate the compound. A HEPES
buffer molecule bound adjacent to the inhibitor in two of the four protein molecules
in the crystals and an array of solvent atoms (red spheres) form an auxiliary van der
Waals surface between the inhibitor and the protein.6
Supplementary data associated with this article can be found, in
Oxadiazoles (e.g., 4f, Table 1) were prepared by combining the
known acid 91 and 4-(trifluoromethoxy)benzamidoxime in the
presence of EDC, then heating the coupled product to close
the ring. After condensation of the oxadiazole, the t-butyl ester
(10, Scheme 2) was carried on to the hydroxamic acid employing
the same transformations used for the tetrazoles. Imidazoles 4h
and 4i were made by unselective alkylation of the required
4- and 5- phenyl imidazoles.
From the data presented in Table 1, we see that the amide in the
MMP-13 selective lead compound 3 (Table 1) could be replaced with
various aryl heterocycle combinations: aryl-tetrazoles (4a–d); -oxa-
diazoles (4f,g); and -imidazoles (4h) affording hydrolytically stable
analogs with impressive selectivity for MMP-13 versus MMP-1, -2, -
7, -8, -9, and -14. Unexpectedly, we found that the 1,5-isomer of the
pyridyl analog (4e) has a selectivity profile very similar to its 2,5-
substituted isomer (4d). These results inspired us to make a
similarly disposed imidazole (4i) and an isomeric 1,5-substituted
tetrazole (4j), where the tetrazole carbon connects to the acyclic
chain instead of the tetrazole nitrogen5 (Scheme 2). Both
compounds were highly selective.
References and notes
1. (a) Barta, T. E.; Becker, D.P.; Freskos, J. N.; Fobian, Y.; Heintz, R.; Kiefer, J. R.;
Mischke, B. V.; Mullins, P. Preceding paper, this Journal.; (b) Becker, D. P.; Barta,
T. E.; Bedell, L. J.; Boehm, T. L.; Bond, B. R.; Carroll, J.; Carron, C. P.; DeCrescenzo,
G. A.; Easton, A. M.; Freskos, J. N.; Funckes-Shippy, C. L.; Heron, M.; Hockerman,
S. L.; Howard, S. C.; Kiefer, J. R.; Li, M. H.; Mathis, K. J.; McDonald, J. J.; Mehta, P.
P.; Munie, G. E.; Sunyer, T.; Swearingen, C. A.; Villamil, C. I.; Welsch, D.;
Williams, J. M.; Yu, Y.; Yao, J. J. Med Chem. 2010, 53, 6653.
2. Kolodziej, S. A.; Hockerman, S. L.; DeCrescenzo, G. A.; McDonald, J. J.; Mischke, D.
A.; Munie, G. E.; Fletcher, T. R.; Stehle, N.; Swearingen, C.; Becker, D. P. Bioorg.
Med. Chem. Lett. 2010, 20, 3561; See also: Kolodziej, S. A.; Hockerman, S. L.;
Boehm, T. L.; DeCrescenzo, G. A.; McDonald, J. J.; Mischke, D. A.; Munie, G. E.;
Fletcher, T. R.; Stehle, N.; Swearingen, C.; Becker, D. P. Bioorg. Med. Chem. Lett.
2010, 20, 3557.
3. For a conceptually related series, see: Wu, J.; Rush, T. S.; Hotchandani, R.; Du, X.;
Geck, M.; Collins, E.; Xu, Z. B.; Skotnicki, J.; Levin, J. I.; Lovering, F. E. Bioorg. Med.
Chem. Lett. 2005, 15, 4105.
4. Komamura, T; Tawara, G.; Yoshihiko, S. JP Patent 63301035 A, 1988; Chem
Abstr. 1989, 111, 105859.
5. De Lombaert, S.; Blanchard, L.; Stamford, L. B.; Tan, J.; Wallace, E. M.; Satoh, Y.;
Fitt, J.; Hoyer, D.; Simonsbergen, D.; Moliterni, J.; Marcopoulos, N.; Savage, P.;
Chou, M.; Trapani, A. J.; Jeng, A. Y. J. Med. Chem. 2000, 43, 488.
6. Coordinates have been deposited in the protein data bank (accession code
3O2X). Crystallographic conditions are detailed in the Supplementary data.
In the course of our research, we solved a 1.9 Å resolution crys-
tal structure of tetrazole 4c (Fig. 2).6 The structure illustrates the