Carboetomidate: A Pyrrole Analog of Etomidate Designed Not to Suppress Adrenocortical Function

Background: Etomidate is a sedative-hypnotic that is often used in critically ill patients because it provides superior hemodynamic stability. However it also binds with high affinity to 11?-hydroxylase, potently suppressing synthesis of steroids by the adrenal gland that are necessary for survival. We report the results of studies to define the pharmacology of (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate), a pyrrole analogue of etomidate specifically designed not to bind with high affinity to 11?-hydroxylase. Methods: The hypnotic potency of carboetomidate was defined in tadpoles and rats using loss of righting reflex assays. Its ability to enhance wild-type ?1?2?2L and etomidate-insensitive mutant ?1?2(M286W)?2L human ?-aminobutyric acid type A receptor activities was assessed using electrophysiological techniques. Its potency for inhibiting in vitro cortisol synthesis was defined using a human adrenocortical cell assay. Its effects on in vivo hemodynamic and adrenocortical function were defined in rats. Results: Carboetomidate was a potent hypnotic in tadpoles and rats. It increased currents mediated by wild-type, but not etomidate-insensitive mutant ?-aminobutyric acid type A receptors. Carboetomidate was three orders of magnitude less potent an inhibitor of in vitro cortisol synthesis by adrenocortical cells than was etomidate. In rats, carboetomidate caused minimal hemodynamic changes and did not suppress adrenocortical function at hypnotic doses. Conclusions: Carboetomidate is an etomidate analogue that retains many of etomidate’s beneficial properties, but is dramatically less potent as an inhibitor of adrenocortical steroid synthesis. Carboetomidate is a promising new sedative-hypnotic for potential use in critically ill patients in whom adrenocortical suppression is undesirable.