2502 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16
Letters
(12) Sorbera, L. A.; Graul, A.; Silvestre, J .; Castaner, J . Bay-12-
9566: oncolytic, antiarthritic, matrix metalloproteinase inhibi-
tor. Drugs Future 1999, 24, 16-21.
(13) O’Brien, P. M.; Ortwine, D. F.; Pavlovsky, A. G.; Picard, J . A.;
Sliskovic, D. R.; Roth, B. D.; Dyer, R. D.; J ohnson, L. L.; Man,
C. F.; Hallak, H. Structure-Activity Relationships and Phar-
macokinetic Analysis for a Series of Potent, Systemically Avail-
able Biphenylsulfonamide Matrix Metalloproteinase Inhibitors.
J . Med. Chem. 2000, 43, 156-166.
(14) (a) Tamura, Y.; Watanabe, F.; Nakatani, T.; Yasui, K.; Fuji, M.;
Komurasaki, T.; Tsuzuki, H.; Maekawa, R.; Yoshioka, T.;
Kawada, K.; Sugita, K.; Ohtani, M. Highly Selective and Orally
Active Inhibitors of Type IV Collagenase (MMP-9 and MMP-2):
N-Sulfonylamino Acid Derivatives. J . Med. Chem. 1998, 41,
640-649, b) Kiyama, R.; Tamura, Y.; Watanabe, F.; Tsuzuki,
H.; Ohtani, M.; Yodo, M. Homology Modeling of Gelatinase
Catalytic Domains and Docking Simulations of Novel Sulfona-
mide Inhibitors. J . Med. Chem. 1999, 42, 1723-1738.
(15) Natchus, M. G.; Bookland, R. G.; Laufersweiler, M. J .; Pikul,
S.; Almstead, N. G.; De, B.; J anusz, M. J .; Hsieh, L. C.; Gu, F.;
Pokross, M. E.; Patel, V. S.; Garver, S. M.; Peng, S. X.; Branch,
T. M.; King, S. L.; Baker, T. R.; Foltz, D. J . and Mieling, G. E.
Development of New Carboxylic Acid-Based MMP Inhibitors
Derived from Functionalized Propargylglycines. J . Med. Chem.
2001, 44, 1060-1071.
(16) (a) Pikul, S.; McDow Dunham, K. L.; Almstead, N. G.; De, B.;
Natchus, M. G.; Anastasio, M. B.; McPhail, S. J .; Snider, C. E.;
Taiwo, Y. O.; Rydel, T.; Dunaway, C. M.; Gu, F.; Meiling, G. E.
Discovery of potent, achiral matrix metalloproteinase inhibitors.
J . Med. Chem. 1998, 41, 3568-3571. (b) Pikul, S.; McDow
Dunham, K. L.; Almstead, N. G.; De, B.; Natchus, M. G.;
Anastasio, M. B.; McPhail, S. J .; Snider, C. E.; Taiwo, Y. O.;
Chen, L.; Dunaway, C. M.; Gu, F.; Meiling, G. E. Design and
synthesis of phosphinamide-based hydroxamic acids as inhibi-
tors of matrix metalloproteinases. J . Med. Chem. 1999, 42, 87-
94. (c) Almstead, N. G.; Bradley, R. S.; Pikul, S.; De, B.; Natchus,
M. G.; Taiwo, Y. O.; Gu, F.; Williams, L. E.; Hynd, B. A.; J anusz,
M. J .; Dunaway, C. M.; Meiling, G. E. Design, Synthesis and
Biological Evaluation of Potent Thiazine and Thiazepine Based
MMP Inhibitors. J . Med. Chem. 1999, 42 (22), 4547-4562. (d)
Cheng, M.; De, B.; Almstead, N. G.; Pikul, S.; Dowty, M. E.;
Dietsch, C. R.; Dunaway, C. M.; Gu, F.; Hsieh, L. C.; J anusz,
M. J .; Taiwo, Y. O.; Natchus, M. G.; Hudlicky, T.; Mandel, M.
Metalloproteinase Inhibitors Derived from a Modified Proline
Scaffold. J . Med. Chem. 1999, 42, 5426-5436. (e) Cheng, M.;
De, B.; Pikul, S.; Almstead, N. G.; Natchus, M. G.; Anastasio,
M. B.; McPhail, S. J .; Snider, C. E.; Taiwo, Y. O.; Chen, L.;
Dunaway, C. M.; Gu, F.; Dowty, M. E.; Meiling, G. E.; J anusz,
M. J .; Wang-Weigand, S. Design and Synthesis of Piperazine
Based MMP Inhibitors. J . Med. Chem. 2000, 43, 369-380. (f)
Natchus, M. G.; Bookland, R. G.; De, B.; Almstead, N. G.; Pikul,
S.; J anusz, M. J .; Heitmeyer, S. A.; Hookfin, E. B.; Hsieh, L. C.;
Dowty, M. E.; Dietsch, C. R.; Patel, V. S.; Garver, S. M.; Gu, F.;
Pokross, M. E.; Mieling, G. E.; Baker, T. R.; Foltz, D. J .; Peng,
S. X.; Bornes, D. M.; Strojnowski, M. J .; Taiwo, Y. O. Develop-
ment of New Hydroxamate Matrix Metalloproteinase Inhibitors
Derived from Functionalized 4-Aminoprolines. J . Med. Chem.
2000, 43, 4948-4963. (g) Pikul, S.; McDow Dunham, K. L.;
Almstead, N. G.; De, B.; Natchus, M. G.; Taiwo, Y. O.; Williams,
L. E.; Hynd, B. A.; Hsieh, L. C.; J anusz, M. J .; Gu, F.; Meiling,
G. E. Heterocycle-based MMP Inhibitors with P2′ Substituents.
Biorg. Med. Chem. Lett. 2001, 11, 1009-1013.
(17) Tullis, J . S.; Laufersweiler, M. J .; VanRens, J . C.; Natchus, M.
G.; Bookland, R. G.; Almstead, N. G.; Pikul, S.; De, B.; Hsieh,
N. C.; J anusz, M. J .; Branch, T. M.; Peng, S. X.; J in, Y. Y.;
Hudlicky, T.; Oppong, K. The Development of New Carboxylic
Acid Based MMP Inhibitors Derived from a Cycloalkylglycine
Scaffold. Biorg. Med. Chem. Lett. In press.
(18) Watanabe, F.; Tsuzuki, H.; Ohtani, M. Preparation of N-
sulfonylamino acid derivatives as metalloproteinase inhibitors.
Int. Appl. WO9727174, 1997.
(19) Analogous N-picolyl group was previously utilized in the design
of hydroxamic acid MMP inhibitors: MacPherson, L. J .; Bayburt,
E. K.; Capparelli, M. P.; Carroll, B. J .; Goldstein, R. L.; Doughty,
J . R.; Spirito, S.; Blancuzzi, V.; Wilson, D.; O’Byrne, E. M.; Ganu,
V. S.; Parker, D. T. Discovery of CGS 27023A, a Non-Peptidic,
Potent, and Orally Active Stromelysin Inhibitor That Blocks
Cartilage Degradation in Rabbits. J . Med. Chem. 1997, 40,
2525-2532.
(20) Both enantiomers were prepared from the corresponding, com-
mercially available N-R-Fmoc-R-[1-(tert-butoxycarbonyl)-4-pip-
eridinyl]glycines as follows: (1) TMSN2, MeOH; (2) H2, Pd/C,
EtOH, 45 psi; (3) MeOC6H4C6H4SO2Cl, Et3N, THF; (4) LiOH,
THF-H2O. Optical purity was determined to be at least 98:2
based on 1H NMR of Mosher esters derived from alcohols
obtained from the corresponding acids (R)-13d and (S)-13d
through reduction with lithium aluminum hydride.
13m and 13n with acceptable levels of protein binding
(93.2% and 90.7%, respectively).
Con clu sion . In summary, a new series of potent and
selective carboxylic acid-based matrix metalloproteinase
inhibitors were discovered. The new design is based on
a substituted piperidine ring attached to the sulfony-
lated glycine at the R position to the carboxylic group.
Many inhibitors based on this design featured unprec-
edented, sub- or low-nanomolar binding to MMP-2, -3,
-8, -9, and -13 when measured at physiological pH of
7.4. These potent interactions were contrasted by rela-
tively weak, micromolar binding to MMP-1 and -7. SAR
studies revealed the importance of the carbamate group
associated with the piperidine ring as well as the
substituents in the P1′ position. The SAR studies also
demonstrated the potential beneficial effects of N-alkyl
substituents on the sulfonamide group. Very good
aqueous solubility of several inhibitors was achieved.
However, this higher solubility did not always lead to
lower binding to plasma protein. Further exploration
of this series is in progress and will be reported in due
course.
Ack n ow led gm en t. The authors thank Mrs. Kelly
M. Solinsky for the synthesis of compound 5 and the
numerous P&GP scientists associated with the MMP
program whose hard work and dedication allowed for
the completion of this work.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the synthesis of 13n and (R)-13d and analytical
data of the target inhibitors described in this paper. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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