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.
Simon Bailey  1 ,  Paul V Fish ,  Stephane Billotte ,  Jon Bordner ,  Doris Greiling ,  Kim James ,  Andrew McElroy ,  James E Mills ,  Charlotte Reed ,  Robert Webster
Affiliations
  • 1. Department of Discovery Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. [email protected]
PMID: 18945617 DOI: 10.1016/j.bmcl.2008.10.036
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.