CNS 7056

Kilpatrick, Gavin J.; McIntyre, Margaret; Cox, Richard F.; Stafford, Jeffrey A.; Pacofsky, Gregory J.; Lovell, Gwyer G; Wiard, Robert P.; Feldman, Paul L.; Collins, Holly A.; Waszczak, Barbara L.; Tilbrook, Gary S

doi:10.1097/01.anes.0000267503.85085.c0

Cited by 243 publications

(152 citation statements)

References 19 publications

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“…Remifentanil and esmolol are examples of soft drugs commonly used by anesthesiologists whereas remimazolam (an analog of midazolam) and AZD3043 (an analog of the hypnotic propanidid) are not yet approved for clinical use, but are in the development pipeline and have reached human trials. 1–5 Pharmaceutical development in anesthesiology has gravitated towards soft drugs because they allow one to quickly respond to rapidly changing clinical needs, which is a significant advantage in the dynamic operating room environment. 6 …”

Section: Introductionmentioning

confidence: 99%

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

Husain

Pejo

et al. 2012

Anesthesiology

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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.

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Section: Introductionmentioning

confidence: 99%

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

Husain

Pejo

et al. 2012

Anesthesiology

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“…2-6 All four metabolites contain an identical carboxylic acid moiety whose pKa is 4.8. 12 Therefore at physiological pH, this moiety is uncharged (i.e., protonated) in 1/400 of all metabolite molecules.…”

Section: Resultsmentioning

confidence: 99%

“…The pharmacological activities of the carboxylic metabolites of remifentanil, esmolol, and remimazolam are orders of magnitude lower than those of their respective parent compounds (4600-fold, 300-fold to 1600-fold, and 300-fold, respectively). 2-6 However, the pharmacologic activity of MOC-etomidate's carboxylic acid metabolite (MOC-ECA) has not been assessed and its potency relative to MOC-etomidate is unknown. We hypothesized that this metabolite possesses significantly lower potency than the parent compound, accounting for the latter's very brief duration of hypnotic action and inability to produce prolonged adrenocortical suppression after bolus administration.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Studies of Methoxycarbonyl Etomidate's Carboxylic Acid Metabolite

Pejo

Haburčák

et al. 2012

Anesthesia &Amp; Analgesia

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Background Methoxycarbonyl etomidate (MOC-etomidate) is a rapidly metabolized and ultra-short acting etomidate analog that does not produce prolonged adrenocortical suppression after bolus administration. Its metabolite (MOC-ECA) is a carboxylic acid whose pharmacology is undefined. We hypothesized that MOC-ECA possesses significantly lower pharmacological activity than MOC-etomidate, accounting for the latter's very brief duration of hypnotic action and inability to produce prolonged adrenocortical suppression after bolus administration. To test this hypothesis, we compared the potencies of MOC-ECA and MOC-etomidate in three biological assays. Methods The hypnotic potency of MOC-ECA was assessed in tadpoles using a loss-of-righting reflexes assay. The gamma-aminobutyric acid type A (GABAA) receptor modulatory potencies of MOC-ECA and MOC-etomidate were compared by defining the concentrations of each required to directly activate α1(L264T)β2γ2L GABAA receptors. The adrenocortical inhibitory potencies of MOC-ECA and MOC-etomidate were compared by defining the concentrations of each required to inhibit in vitro cortisol production by adrenocortical cells. Results MOC-ECA's EC50 for loss-of-righting reflexes in tadpoles was 2.8 ± 0.64 mM as compared to a previously reported value of 8 ± 2 μM for MOC-etomidate. EC50s for direct activation of GABAA receptors were 3.5 ± 0.63 mM for MOC-ECA versus 10 ± 2.5 μM for MOC-etomidate. IC50 for inhibiting in vitro cortisol production by adrenocortical cells was 30 ± 7 μM for MOC-ECA versus 0.10 ± 0.02 μM for MOC-etomidate. Conclusions In all three biological assays, MOC-ECA's potency was approximately 300-fold lower than that of MOC-etomidate.

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“…It has emerged from its initial animal experiments, and human studies are underway to determine its place in anesthesiologists armamentarium. [1234] A word of caution to tamper the optimism is warranted. Anesthesia literature is rich with “promising” drugs, rapacuronium, mivacuronium, althesin are just a few examples.…”

Section: Introductionmentioning

confidence: 99%

Remimazolam: The future of its sedative potential

Goudra

Singh

2014

Saudi J Anaesth

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Remimazolam (CNS 7056) is a new drug innovation in anesthesia. It combines the properties of two unique drugs already established in anesthesia – Midazolam and remifentanil. It acts on GABA receptors like midazolam and has organ-independent metabolism like remifentanil. It is likely to be the sedative of the future, as preliminary phase II trials have shown minimal residual effects on prolonged infusions. It has potential to be used as a sedative in ICU and as a novel agent for procedural sedation. Unlike most rapidly acting intravenous sedatives available presently, the propensity to cause apnea is very low. Availability of a specific antagonist (flumazenil) adds to its safety even in cases of overdose. The present review discusses remimazolam's potential as a new drug in anesthesia along with the presently available literary evidence.

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CNS 7056

Cited by 243 publications

References 19 publications

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

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

Pharmacological Studies of Methoxycarbonyl Etomidate's Carboxylic Acid Metabolite

Remimazolam: The future of its sedative potential

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