Husain, S. Shaukat; Pejo, Ervin; Ge, Rile; Raines, Douglas E. published an article in 2012, the title of the article was Modifying Methoxycarbonyl Etomidate Inter-Ester Spacer Optimizes In Vitro Metabolic Stability and In Vivo Hypnotic Potency and Duration of Action.Safety of (R)-Methyl 3-hydroxybutanoate And the article contains the following content:
Background: Methoxycarbonyl etomidate is the prototypical very rapidly metabolized etomidate analog. Initial studies suggest that it may be too short acting for many clin. uses. We hypothesized that its duration of action could be lengthened and clin. utility broadened by incorporating specific aliphatic groups into the mol. 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 chromatog. 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 vs. 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 the too-brief duration of action for methoxycarbonyl etomidate. This work may provide a blueprint for optimizing the pharmacol. properties of other soft drugs. The experimental process involved the reaction of (R)-Methyl 3-hydroxybutanoate(cas: 3976-69-0).Safety of (R)-Methyl 3-hydroxybutanoate
The Article related to methoxy carbonyl etomidate analog hypnotic metabolism pharmacodynamic pharmacokinetic msbar, Pharmacology: Structure-Activity and other aspects.Safety of (R)-Methyl 3-hydroxybutanoate
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