Investigation of anticholinergic and non-steroidal anti-inflammatory prodrugs which reduce chemically induced skin inflammation

Sherri C. Young, Karine M. Fabio, Mou Tuan Huang, Jaya Saxena, Meredith P. Harman, Christophe D. Guillon, Anna M. Vetrano, Diane E. Heck, Robert A. Flowers, Ned D. Heindel, Jeffrey D. Laskin

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

As part of a continuous effort to develop efficient counter measures against sulfur mustard injuries, several unique NSAID prodrugs have been developed and screened for anti-inflammatory properties. Presented herein are three classes of prodrugs which dually target inflammation and cholinergic dysfunction. Compounds 1-28 contain common NSAIDs linked either to choline bioisosteres or to structural analogs of acetylcholinesterase (AChE) inhibitors. These agents have shown utility as anti-vesicants and anti-inflammatory agents when screened in a mouse ear vesicant model (MEVM) against both 2-chloroethyl ethyl sulfide (CEES), a blistering agent, and 12-O-tetradecanoylphorbol-13-acetate (TPA), a common topical irritant. Many of the prodrugs have activity against CEES, with 5, 18, 22 and 27 reducing inflammation by more than 75% compared with a control. Compounds 12, 13, 15 and 22 show comparable activity against TPA. Promising activity in the MEVM is related to half-lives of NSAID release in plasma, moderate to high lipophilicity, and some degree of inhibition of AChE, a potential contributor to sulfur mustard-mediated tissue damage.

Original languageEnglish (US)
Pages (from-to)135-141
Number of pages7
JournalJournal of Applied Toxicology
Volume32
Issue number2
DOIs
StatePublished - Feb 2012

All Science Journal Classification (ASJC) codes

  • Toxicology

Keywords

  • Anti-inflammatory
  • Anticholinergic
  • CEES
  • NSAID prodrug
  • Sulfur mustard
  • TPA
  • Topical treatment

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