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Orally active MMP-1 sparing α-tetrahydropyranyl and α-piperidinyl sulfone matrix metalloproteinase (MMP) inhibitors with efficacy in cancer, arthritis, and cardiovascular disease.

Abstract
α-Sulfone-α-piperidine and α-tetrahydropyranyl hydroxamates were explored that are potent inhibitors 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. α-Piperidine 19v (SC-78080/SD-2590) was selected for development toward the initial indication of cancer, while α-piperidine and α-tetrahydropyranyl hydroxamates 19w (SC-77964) and 9i (SC-77774), respectively, were identified as backup compounds.
AuthorsDaniel 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, Jun Yao
JournalJournal of medicinal chemistry (J Med Chem) Vol. 53 Issue 18 Pg. 6653-80 (Sep 23 2010) ISSN: 1520-4804 [Electronic] United States
PMID20726512 (Publication Type: Journal Article)
Chemical References
  • 1-cyclopropyl-N-hydroxy-4-(4-(4-(trifluoromethoxy)phenoxy)phenylsulfonyl)piperidine-4-carboxamide
  • Anti-Inflammatory Agents
  • Antineoplastic Agents
  • Cardiovascular Agents
  • Hydroxamic Acids
  • Matrix Metalloproteinase Inhibitors
  • N-hydroxy-1-(2-methoxyethyl)-4-((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)piperidine-4-carboxamide
  • N-hydroxy-4-((4-(4-(trifluoromethyl)phenoxy)phenyl)sulfonyl)tetrahydro-2H-pyran-4-carboxamide
  • Piperidines
  • Pyrans
  • Sulfones
Topics
  • Animals
  • Anti-Inflammatory Agents (chemical synthesis, chemistry, pharmacology)
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Biological Availability
  • Cardiovascular Agents (chemical synthesis, chemistry, pharmacology)
  • Cartilage, Articular (drug effects, pathology)
  • Cattle
  • Crystallography, X-Ray
  • Humans
  • Hydroxamic Acids (chemical synthesis, chemistry, pharmacology)
  • Hypertrophy, Left Ventricular (drug therapy)
  • Macaca fascicularis
  • Matrix Metalloproteinase Inhibitors
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Molecular Structure
  • Piperidines (chemical synthesis, chemistry, pharmacology)
  • Pyrans (chemical synthesis, chemistry, pharmacology)
  • Rats
  • Structure-Activity Relationship
  • Sulfones (chemical synthesis, chemistry, pharmacology)
  • Xenograft Model Antitumor Assays

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