Modifying Methoxycarbonyl Etomidate Inter-Ester Spacer Optimizes In Vitro  Metabolic Stability and In Vivo  Hypnotic Potency and Duration of Action

Abstract

Background Methoxycarbonyl etomidate is the prototypical ultra-rapidly metabolized etomidate analog. Initial studies suggest that it may be too short acting for many clinical uses. We hypothesized that its duration of action could be lengthened and clinical utility broadened by incorporating specific aliphatic groups into the molecule to sterically protect its ester moiety from esterase-catalyzed hydrolysis. To test this hypothesis, we developed a series of methoxycarbonyl etomidate analogs (spacer-linked etomidate esters) containing various aliphatic protecting groups and spacer lengths. Methods Spacer-linked etomidate esters were synthesized and their hypnotic potencies and durations of action following bolus administration were measured in rats using a loss of righting reflexes assay. Octanol:water partition coefficients and metabolic half-lives in pooled rat blood were determined chromatographically. Results All spacer-linked etomidate esters produced hypnosis rapidly and in a dose-dependent manner. ED50s for loss of righting reflexes ranged from 0.69 ± 0.04 mg/kg for cyclopropyl-methoxycarbonyl metomidate to 11.1 ± 0.8 mg/kg for methoxycarbonyl metomidate. The slope of a plot of the duration of loss of righting reflexes versus the logarithm of the dose ranged 12-fold among spacer-linked etomidate esters, implying widely varying brain clearance rates. The in vitro metabolic half-lives of these compounds in rat blood varied by more than two orders of magnitude and were diastereometrically-selective. Conclusions We created 13 new analogs of methoxycarbonyl etomidate and identified two that have significantly higher potency and potentially address methoxycarbonyl etomidate’s too brief duration of action. This work may provide a blueprint for optimizing the pharmacological properties of other soft drugs.

Advancing Novel Anesthetics

“…In both species, anesthetic induction is fast and hypnotic potency is high (hypnotic ED 50 ~ 0.8 mg/kg and 0.69 mg/kg in dogs and rats, respectively). 23 The duration of hypnosis increases approximately linearly with the logarithm of the dose in both species with slopes for this relationship that are similar (9.9 and 6.9 in dogs and rats, respectively). 23 In dogs and rats, hypnotic recovery times are independent of infusion duration and occur on similar time-scales following 2-h continuous CPMM infusions (5.5 min and 4.2 min in dogs and rats, respectively).…”

“…23 The formulated drug was stored frozen at -20°C with ongoing stability testing of representative batches demonstrating no significant degradation over time. Etomidate was purchased from BaChem (Torrance, CA) and formulated (2 mg/ml) as an aqueous solution in 35% propylene glycol.…”

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

“…8 Such substrate selectivity is not uncommon among esterases and may be leveraged to fine tune the pharmacology of soft drugs. 24–26 This finding also suggests that the esterases responsible for metabolizing these drugs in the brain are different from those in the blood.…”

“…8 Of these new compounds, cyclopropyl methoxycarbonyl metomidate (CPMM) possessed the most promising pharmacology in animals (Figure 1B) because it exhibited the highest potency and produced hypnosis that reversed within several minutes after stopping continuous infusions lasting as long as 2 hours. 7,8,11 CPMM is now undergoing trials in humans.…”

Toward a Better Etomidate

“…Duration of LORR Rats is an estimate of the time required for a rat to recover its righting reflex following of an IV dose 4 times the ED 50 dose required for LORR. The half-life in blood was determined by in vitro high-performance liquid chromatography analysis of heparinized rat blood at 37°C into which 200 µM drug had been added 13,14. …”