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 (R³OCONR¹R²), 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 ~ Alkyl-OCO-N(Alkyl)₂ ≥ Alkyl-OCO-N(endocyclic) ≥ Aryl-OCO-N(Alkyl)₂ ~ Aryl-OCO-N(endocyclic) ≥ Alkyl-OCO-NHAryl ~ Alkyl-OCO-NHAcyl >> Alkyl-OCO-NH₂ > Cyclic carbamates. This trend should prove useful in the design of carbamates as drugs or prodrugs.