Qualitative structure-metabolism relationships in the hydrolysis of carbamates

The aims of this review were 1) to compile a large number of reliable literature data on the metabolic hydrolysis of medicinal carbamates and 2) to extract from such data a qualitative relation between molecular structure and lability to metabolic hydrolysis. The compounds were classified according to the nature of their substituents ((ROCONRR2)-O-3-R-1), and a metabolic lability score was calculated for each class. A trend emerged, such that the metabolic lability of carbamates decreased (i.e., their metabolic stability increased), in the following series: Aryl-OCO-NHAlkyl >> Alkyl-OCO-NHAlkyl similar to Alkyl-OCO-N(Alkyl)(2) >= Alkyl-OCO-N(endocyclic) >= Aryl-OCO-N(Alkyl)(2) similar to Aryl-OCO-N(endocyclic) >= Alkyl-OCO-NHAryl similar to Alkyl-OCO-NHAcyl >> Alkyl-OCO-NH2 > Cyclic carbamates. This trend should prove useful in the design of carbamates as drugs or prodrugs.