Cyclic carbamates in medicine: A clinical perspective.

Carbamate group is mainly used for designing prodrugs to achieve first-pass and systemic stability against enzyme hydrolysis as the carbamate functionality is recognized by esterase enzymes. As compared to the ester functionality, the carbamate group shows a lesser lability towards enzyme hydrolysis, but a higher susceptibility than amides. Cyclic carbamates present a unique motif in the contemporary drug discovery and development owing to the presence of a polar, and sterically small, constrained Hydrogen-bonding acceptor atom. The metabolic stability of 5/6-membered cyclic carbamates are higher as compared to their acyclic counterparts as the former do not undergo metabolic ring opening under physiological conditions. Besides, the metabolic lability of acyclic carbamates is determined by the degree of substitution at the endocyclic/exocyclic "N" atom, which further enables the design and development of various carbamate drugs or prodrugs. As such, the metabolic stability of carbamates follows the order: Cyclic carbamates > Alkyl-OCO-NH  » Alkyl-OCO-NHAcyl ∼ Alkyl-OCO-NHAryl ≥ Aryl-OCO-N(endocyclic) ∼ Aryl-OCO-N(Alkyl)  ≥ Alkyl-OCO-N(endocyclic) ≥ Alkyl-OCO-N(Alkyl)  ∼ Alkyl-OCO-NHAlkyl » Aryl-OCO-NHAlkyl.