Succinyl hydroxamates as potent and selective non-peptidic inhibitors of procollagen C-proteinase: design, synthesis, and evaluation as topically applied, dermal anti-scarring agents

Bioorg Med Chem Lett. 2008 Dec 15;18(24):6562-7. doi: 10.1016/j.bmcl.2008.10.036. Epub 2008 Oct 11.

Abstract

Succinyl hydroxamates 1 and 2 are disclosed as novel series of potent and selective inhibitors of procollagen C-proteinase (PCP) which may have potential as anti-fibrotic agents. Carboxamide 7 demonstrated good PCP inhibition and had excellent selectivity over MMPs involved in wound healing. In addition, 7 was effective in a cell-based model of collagen deposition (fibroplasia model) and was very effective at penetrating human skin in vitro. Compound 7 (UK-383,367) was selected as a candidate for evaluation in clinical studies as a topically applied, dermal anti-scarring agent.

MeSH terms

  • Administration, Cutaneous
  • Bone Morphogenetic Protein 1 / chemistry*
  • Cell Line, Tumor
  • Chemistry, Pharmaceutical / methods*
  • Cicatrix / drug therapy*
  • Cicatrix, Hypertrophic / drug therapy*
  • Drug Design
  • Epidermis / drug effects
  • Fibrosis / pathology
  • Humans
  • Hydroxamic Acids / chemistry*
  • Inhibitory Concentration 50
  • Models, Chemical
  • Molecular Conformation
  • Oxazoles / chemistry

Substances

  • Hydroxamic Acids
  • Oxazoles
  • BMP1 protein, human
  • Bone Morphogenetic Protein 1