Methoxycarbonyl-etomidate

Abstract

Background Etomidate is a rapidly-acting sedative-hypnotic that provides hemodynamic stability. However because it causes prolonged suppression of adrenocortical steroid synthesis, its clinical utility and safety are limited. We describe the results of studies to define the pharmacology of (R)-3-methoxy-3-oxopropyl1-(1-phenylethyl)-1H-imidazole-5-carboxylate (MOC-etomidate), the first etomidate analogue designed to be susceptible to ultra-rapid metabolism. Methods The γ-aminobutyric acid type A receptor activities of MOC-etomidate and etomidate were compared using electrophysiological techniques in human α1β2γ2L receptors. MOC-etomidate’s hypnotic concentration was determined in tadpoles using a loss of righting reflex assay. Its in-vitro metabolic half-life was measured in human liver S9 fraction and the resulting metabolite provisionally identified using high performance liquid chromatography/mass spectrometry techniques. The hypnotic and hemodynamic actions of MOC-etomidate, etomidate, and propofol were defined in rats. The abilities of MOC-etomidate and etomidate to inhibit corticosterone production were assessed in rats. Results MOC-etomidate potently enhanced γ-aminobutyric acid type A receptor function and produced loss of righting reflex in tadpoles. Metabolism in human liver S9 fraction was first-order with an in-vitro half-life of 4.4 min versus > 40 min for etomidate. MOC-etomidate’s only detectable metabolite was a carboxylic acid. In rats, MOC-etomidate produced rapid loss of righting reflex that was extremely brief and caused minimal hemodynamic changes. Unlike etomidate, MOC-etomidate produced no adrenocortical suppression 30 minutes after administration. Conclusions MOC-etomidate is an etomidate analogue that retains etomidate’s important favorable pharmacological properties. However, it is rapidly metabolized, ultra-short acting, and does not produce prolonged adrenocortical suppression following bolus administration.

Distinct Hypnotic Recoveries After Infusions of Methoxycarbonyl Etomidate and Cyclopropyl Methoxycarbonyl Metomidate

“…5–12 Our primarily goal was to create a drug that would retain etomidate’s highly desirable properties, but whose effects on adrenocortical function would lift quickly after drug administration because the drug was rapidly eliminated. At the same time, it was hoped that recovery from the drug’s hypnotic action would similarly be very rapid even after prolonged infusion.…”

“…5 Similar to remifentanil and esmolol, it contains a metabolically labile ester moiety that is linked to the pharmacophore via a 2-carbon spacer. This spacer facilitates hydrolysis by esterases by reducing steric hindrance around the ester.…”

“…5-min) continuous infusions, MOC-etomidate had an ultra-short duration of hypnotic action (~1 minute) and did not produce persistent adrenocortical suppression. 5,6 However with longer infusions (e.g. 30-min) that required the administration of larger quantities of MOC-etomidate, hypnotic recovery slowed dramatically as MOC-etomidate’s carboxylic acid metabolite (MOC-ECA) accumulated to levels in both blood and cerebrospinal fluid (CSF) that were sufficient to produce hypnosis.…”

Advancing Novel Anesthetics

“…19 We established proof-of-principle by synthesizing the prototypical “soft” ( i.e. , metabolically-labile) etomidate analogue methoxycarbonyl etomidate, but found that its pharmacological properties were not suitable for clinical development.…”

“…, metabolically-labile) etomidate analogue methoxycarbonyl etomidate, but found that its pharmacological properties were not suitable for clinical development. 19-22 Subsequent efforts at rational optimization of methoxycarbonyl etomidate's pharmacology led to the synthesis and study of more than a dozen new analogues, of which cyclopropylmethoxycarbonyl metomidate (CPMM, also known as ABP-700) exhibited the most promising pharmacology in rats (fig. 1) and became the lead candidate for advancement to human trials.…”