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

J Appl Toxicol. 2012 Feb;32(2):135-41. doi: 10.1002/jat.1645. Epub 2011 Feb 11.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylcholinesterase
  • Administration, Topical
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Chemical Warfare Agents / toxicity
  • Cholinergic Antagonists / chemistry
  • Cholinergic Antagonists / therapeutic use*
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / therapeutic use
  • Disease Models, Animal
  • Ear / pathology
  • Female
  • Humans
  • Inflammation / chemically induced
  • Inflammation / drug therapy*
  • Inflammation / pathology
  • Irritants / toxicity
  • Mice
  • Mustard Gas / analogs & derivatives
  • Mustard Gas / toxicity*
  • Prodrugs / chemistry
  • Prodrugs / therapeutic use*
  • Skin / drug effects
  • Skin / injuries*
  • Tetradecanoylphorbol Acetate / toxicity

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Chemical Warfare Agents
  • Cholinergic Antagonists
  • Cholinesterase Inhibitors
  • Irritants
  • Prodrugs
  • 2-chloroethyl ethyl sulfide
  • Acetylcholinesterase
  • Tetradecanoylphorbol Acetate
  • Mustard Gas