Alkylcarbamic acid aryl esters

Tarzia et al. [69, 70] have recently reported the FAAH inhibitory activity of a series of alkylcarbamic acid aryl esters. The starting point for their studies was the known serine hydrolase inhibitor carbamyl (51) that had no activity at FAAH. Replacement of the small methyl group of carbamyl (51) with more lipophilic groups and, in particular, bulky lipophilic groups resulted in increased affinity at FAAH (Table 6.6). Exploration of replacements of the naphthyl moiety revealed that replacement with a biphenyl group resulted in improved affinity and in particular, the 3-biphenylyl group proved effective... 

Tarzia, G., Duranti, A., Tontini, A., Piersanti, G., Mor, M., Rivara, S., Plazzi, P. V., Park, C., Kathuria, S., and Piomelli, D. (2003). Design, synthesis, and structure-activity relationships of alkylcarbamic acid aryl esters, a new class of fatty acidamide hydrolase inhibitors. J. Med. Chem. 

Another series of irreversible inhibitors—alkylcarbamic acid aryl esters, with apparent specificity for FAAH—has also been reported (Kathuria et al. 2003 Tarzia et al. 2003). These inhibitors, which do not bind to CB or CB2 receptors or inhibit MGL or AEA cellular uptake, act by carbamoylation of the active site serine residue. The most potent of the series is URB597 (Kathuria et al. 2003). Of added significance is that these analogs, although difficult to emulsify, are also active as inhibitors of FAAH in vivo, resulting in an elevation of brain AEA content of approximately threefold at a dose of 0.3 mg/kg without an effect on the content of 2-AG (Kathuria et al. 2003). 

Of the N-alkylcarbamates only the aryl esters of N-alkylcarbamic acid possess herbicidal activity. The herbicidal activity of N-alkylcarbamic acid alkylesters and of the heterocyclic derivatives of N-alkylcarbamic add is mentioned only in the patents literature, but these latter derivatives have not found agricultural application. Examples are the N-dimethylcarbamic acid enol esters proposed by Whetstone and Kuddema (1959) and the N-methylcarbamic add pyridine esters proposed by Johnston (1964). 

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