Qualitative structure-metabolism relationships in the hydrolysis of carbamates

Abstract

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.

Keywords::

• Carbamates
• structure-property relationships (SPR)
• hydrolysis
• metabolic stability
• drug metabolism

Acknowledgements

The authors are grateful to Emeritus Prof. Pier Vincenzo Plazzi for his kind interest during the early phases of the project

Declaration of interest

Research support from the University of Parma is gratefully acknowledged. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.