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 countermeasures 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 to 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.

Therapeutic potential of a non-steroidal bifunctional anti-inflammatory and anti-cholinergic agent against skin injury induced by sulfur mustard

“…NDH 4338 is a bifunctional NSAID-AChEI anti-inflammatory compound designed to target SM-induced cutaneous injury by inhibiting AChE and releasing an NSAID in vivo (Young et al , 2012). The NSAID moiety, indomethacin, is a non-selective COX inhibitor, which has been shown to display limited efficacy against SM in the mouse ear vesicant model (MEVM) (Casillas et al , 2000).…”

“…The neurotransmitter, acetylcholine and cholinergic enzymes are produced by keratinocytes and infiltrating leukocytes during inflammatory responses; the skin cholinergic system is thought to regulate keratinocyte proliferation, differentiation, adhesion, and migration (Grando, 1997; Kurzen et al , 2007). NDH 4338 was first reported to show efficacy against half mustard-induced edema in the mouse ear vesicant model (Young et al , 2010; Young et al , 2012). The present studies demonstrate that NDH 4338 can also protect, at least in part, the dorsal skin of hairless mice from SM-induced injury; these findings suggest that NDH 4338 may be useful as a countermeasure against vesicant-induced skin injury.…”

“…Indomethacin is tethered by ester and carbonate linkages to 3, 3-dimethyl-1-butanol, an anti-cholinergic choline bioisostere (Figure 1). This compound, referred to as NDH 4338, possesses anti-inflammatory activity and is an AChEI inhibitor (Young et al , 2010; Young et al , 2012). In previous studies using the mouse ear vesicant model we demonstrated that NDH 4338 mitigated skin inflammation induced by the half mustard vesicant, 2-chloroetheyl ethyl sulfide (CEES) and was shown to reduce edema by over 90%, suggesting its use as a countermeasure against SM-induced skin injury (Young et al , 2010; Young et al , 2012).…”

Mustard vesicants alter expression of the endocannabinoid system in mouse skin

“…All experiments with SM were performed at MRIGlobal (Kansas City, MO). The efficacy of candidate FAAH inhibitors was evaluated using a mouse ear vesicant model (MEVM) as previously described (Babin et al, 2000; Casillas et al, 2000; Young et al, 2012) using the sulfur mustard analog 2-chloroethyl ethyl sulfide to induce inflammation. For NM dorsal skin and MEVM experiments CD1 mice were used as they were less costly than SKH1-Hr mice.…”

N<sup>ω</sup>-Nitro-N<sup>ω’</sup>-Substituted Guanidines: A Simple Class of Nitric Oxide Synthase Inhibitors

“…[20] In this assay 4 showed 41% suppression of inflammation compared to classic anti-inflammatory standards such as S-naproxen (11%), diclofenac (17%), indomethacin (46%), menthol (53%), or farnesol (64%). [21] These simple guanidine mimics of the natural substrate of the enzyme, L-arginine, demonstrate that the amino acid portion of that substrate is not required to achieve activity and even selectivity toward the nNOS isoform. Guanidines can be considered a potential platform from which a more in depth SAR could be built and one that could yield even better inhibitors.…”