有机小分子探针合成与脱保护文献.pdfVIP

J. Med. Chem. 2010, 53, 6653–6680 6653 DOI: 10.1021/jm100669j Orally Active MMP-1 Sparing r-Tetrahydropyranyl and r-Piperidinyl Sulfone Matrix Metalloproteinase (MMP) Inhibitors with Efficacy in Cancer, Arthritis, and Cardiovascular Disease Daniel P. Becker,* Thomas E. Barta, Louis J. Bedell, Terri L. Boehm, Brian R. Bond,† Jeffery Carroll, Chris P. Carron,‡ Gary A. DeCrescenzo, Alan M. Easton, John N. Freskos, Chris L. Funckes-Shippy, Marcia Heron, Susan Hockerman, Carol Pearcy Howard, James R. Kiefer,§ Madeleine H. Li, Karl J. Mathis, Joseph J. McDonald, Pramod P. Mehta, Grace E. Munie, ) Teresa Sunyer, Craig A. Swearingen, Clara I. Villamil, Dean Welsch, Jennifer M. Williams, Ying Yu, and Jun Yao Pfizer Research, 700 Chesterfield Village Parkway, St. Louis, Missouri 63198. †Contact for cardiovascular biology: E-mail, bbond4@. ‡ Contact for cancer biology: E-mail, chris.p.carron@. Current address: Monsanto Company C3NG, 800 North Lindbergh Boulevard, St. Louis, MO 63167. § Contact for crystallography and computational chemistry: E-mail, james.kiefer@. ) Contact for arthritis biology: E-mail, dean.j.welsch@. Received June 2, 2010 R-Sulfone-R-piperidine and R-tetrahydropyranyl hydroxamates were explored that are potent inhibi- tors of MMP’s-2, -9, and -13 that spare MMP-1, with oral efficacy in inhibiting tumor growth in mice and left-ventricular hypertrophy in rats and in the bovine cartilage degradation ex vivo explant system. R-Piperidine 19v (SC-78080/SD-2590) was selected for development toward the initial indication of cancer, while R-piperidine a