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

J Med Chem. 2010 Sep 23;53(18):6653-80. doi: 10.1021/jm100669j.

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.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemical synthesis*
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Biological Availability
  • Cardiovascular Agents / chemical synthesis*
  • Cardiovascular Agents / chemistry
  • Cardiovascular Agents / pharmacology
  • Cartilage, Articular / drug effects
  • Cartilage, Articular / pathology
  • Cattle
  • Crystallography, X-Ray
  • Humans
  • Hydroxamic Acids / chemical synthesis*
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacology
  • Hypertrophy, Left Ventricular / drug therapy
  • Macaca fascicularis
  • Matrix Metalloproteinase Inhibitors*
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Molecular Structure
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / pharmacology
  • Pyrans / chemical synthesis*
  • Pyrans / chemistry
  • Pyrans / pharmacology
  • Rats
  • Structure-Activity Relationship
  • Sulfones / chemical synthesis*
  • Sulfones / chemistry
  • Sulfones / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • 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