Carbamates inhibitors

A series of dioxane carbamate inhibitors has recently been disclosed by Sanofi-Aventis. No biological data are provided for specific compounds, although most compounds are described as having IC50 values for FAAH inhibition ranging from 0.005-1 Compound (59) is one of over 25 compounds specifically claimed [74]. 

C. Morisseau, G. Du, J. W. Newman, B. D. Hammock, Mechanism of Mammalian Soluble Epoxide Hydrolase by Chalcone Oxide Derivatives , Arch. Biochem. Biophys. 1998, 356, 214 - 228 C. Morisseau, M. H. Goodrow, D. Dowdy, J. Zheng, J. F. Greene, J. R. Sanborn, B. D. Hammock, Potent Urea and Carbamate Inhibitors of Soluble Epoxide Hydrolases , Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 8849 - 8854. 

Pralidoxime is administered by intravenous infusion, 1-2 g given over 15-30 minutes. In spite of the likelihood of aging of the phosphate-enzyme complex, recent reports suggest that administration of multiple doses of pralidoxime over several days may be useful in severe poisoning. In excessive doses, pralidoxime can induce neuromuscular weakness and other adverse effects. Pralidoxime is not recommended for the reversal of inhibition of acetylcholinesterase by carbamate inhibitors. Further details of treatment of anticholinesterase toxicity are given in Chapter 58. 

Incubation of AChE with onchidal resulted in the production of acetate, demonstrating that onchidal was a substrate for AChE, and approximately 3250 mol of onchidal was hydrolyzed/mol of enzyme irreversibly inhibited. Organophosphate and carbamate inhibitors of AChE have partition ratios (mol of toxin hydrolyzed/mol of enzyme irreversibly inhibited) that approach unity. Therefore, the relatively high partition ratio for onchidal suggests that the mechanism of inhibition utilized by onchidal may be distinctly different from other irreversible inhibitors (Walsh, 1984). The rate of hydrolysis of onchidal (Acat) was 325 min this value is relatively slow suggesting that onchidal is not a very good substrate. The ability of AChE to hydrolyze onchidal raised the question of whether inhibition of enzyme activity resulted from onchidal itself or from a product of the enzymatic hydrolysis of onchidal. Enzyme kinetics revealed that onchidal was unable to completely inhibit higher concentrations of AChE. From the experiments performed by Abramson et al. (1989), onchidal was in molar excess and was completely hydrolyzed. Thus,... 

Initially, inhibitors of this class form complexes in which the inhibitor is attached to the enzyme at both anionic and esteratic sites subsequently, hydrolysis proceeds In a manner analogous to chat of ACh, and the alcoholic moiety Is split off, leaving a carbamylaced and inhibited enzyme. Later, this enzyme reacts with water to release a substituted carbamlc acid and the regenerated enzyme. The main difference between the reaction of Che natural substrate, ACh, and that of the carbamate Inhibitors is the velocity of Che final step the half-life of dimethylcacbamyl AChE, formed by the reaction with neostigmine, is more than 40 million times chat of the acetylaced enzyme 30 min and 42. ms, respectively (15). 

RIvastIgmine. Rivasligmine (Exelon. EA 713) is a pseudoirreversibic noncompetitive carbamate inhibitor of AChE. Although the half-life is approximately 2 hours, the inhibitory properties of this agent last for 10 hours because of the slow dissociation of the drug from the enzyme. The FDA approved its use in mild-lo-moderalc Alzheimer s disease in April 2000. 

More recently, a series of irreversible aryl-carbamates inhibitors were described (Mor et al., 2004). URB597 (cyclohexyl carbamic acid 3 -carbamoyl-biphenyl-3-yl ester) (Table 4.1), the most potent member of this family, inhibited FAAH activity with an IC50 value of 4.6 nM in rat brain extracts (Mor et al,... 

Aryl carbamates are superior to alkyl carbamates as AChEls, because they have better affinity for AChE and, therefore, carbamylafe AChE more efficiently. Physostigmine and other aryl carbamates exhibit inhibition constants (Ki) on the order of 10 to 10 ° M and are three to four orders of magnitude more effective than alkyl carbamates, such as carbachol (Ki - 10 M). This is to be expected, because phenoxide anions are more stable than and, hence, are better leaving groups than alkoxide anions. Phenoxide anions are stabilized through resonance with the aromatic ring. Thus, the therapeutically effective carbamate inhibitors of AChE are derived from phenols. 

E = AChE CX = Carbamate Inhibitor EC = Carbamoylated AChE ECX Receptor Complex X = Phenolate Leaving Group... 

Critical Differences in the Binding of Aryl Phosphate and Carbamate Inhibitors of Acetylcholinesterases... 

In spite of the continuing search for an improved muscarinic cholinergic blocking agent, atropine and its salts are still most widely used in the treatment of intoxication by organophosphate and carbamate inhibitors of cholinesterase. Therefore, the characteristics of this compound in the... 

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