title: Investigation of anticholinergic and non-steroidal anti-inflammatory prodrugs which reduce chemically induced skin inflammation.
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.
authors.affiliation: Department of Chemistry, Lehigh University, Bethlehem, PA 18015, USA.
authors.forename: Sherri C
authors.initials: SC
authors.lastname: Young
authors.forename: Karine M
authors.initials: KM
authors.lastname: Fabio
authors.forename: Mou-Tuan
authors.initials: MT
authors.lastname: Huang
authors.forename: Jaya
authors.initials: J
authors.lastname: Saxena
authors.forename: Meredith P
authors.initials: MP
authors.lastname: Harman
authors.forename: Christophe D
authors.initials: CD
authors.lastname: Guillon
authors.forename: Anna M
authors.initials: AM
authors.lastname: Vetrano
authors.forename: Diane E
authors.initials: DE
authors.lastname: Heck
authors.forename: Robert A
authors.initials: RA
authors.lastname: Flowers
authors.forename: Ned D
authors.initials: ND
authors.lastname: Heindel
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Laskin
mesh_terms: D000110:Acetylcholinesterase; D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000627:therapeutic use*; D002619:Chemical Warfare Agents / Q000633:toxicity; D018680:Cholinergic Antagonists / Q000737:chemistry / Q000627:therapeutic use*; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D004195:Disease Models, Animal; D004423:Ear / Q000473:pathology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D007509:Irritants / Q000633:toxicity; D051379:Mice; D009151:Mustard Gas / Q000031:analogs & derivatives / Q000633:toxicity*; D011355:Prodrugs / Q000737:chemistry / Q000627:therapeutic use*; D012867:Skin / Q000187:drug effects / Q000293:injuries*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002619:Chemical Warfare Agents; D018680:Cholinergic Antagonists; D002800:Cholinesterase Inhibitors; D007509:Irritants; D011355:Prodrugs; C031278:2-chloroethyl ethyl sulfide; D000110:Acetylcholinesterase; D013755:Tetradecanoylphorbol Acetate; D009151:Mustard Gas