DL-1-(1-Arylalkyl)imidazole-5-carboxylate Esters. A Novel Type of Hypnotic Agents

Godefroi, Erik F.; Janßen, Paul; Eycken, Cyriel A. M. Van der; Heertum, Albert H. M. T. Van; Niemegeers, C. J. E.

doi:10.1021/jm00326a017

Cited by 79 publications

(73 citation statements)

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“…Etomidate is an imidazole derivative that was initially developed in 1965 as a potential chemotherapeutic agent (79). Early studies in animal models, however, demonstrated that it induced rapid-onset reversible sedation and hypnosis in rats (79).…”

Section: Etomidatementioning

confidence: 99%

“…Early studies in animal models, however, demonstrated that it induced rapid-onset reversible sedation and hypnosis in rats (79). It was therefore introduced to clinical practice as an anaesthetic agent in 1972.…”

Section: Etomidatementioning

confidence: 99%

“…It was therefore introduced to clinical practice as an anaesthetic agent in 1972. As a hypnotic agent, it has a unique safety profile with a rapid-onset and short duration of action as well as a very high therapeutic ratio (lethal dose is 12 times the hypnotic dose) compared with other hypnotics such as barbiturates (79).…”

Section: Etomidatementioning

confidence: 99%

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THERAPY OF ENDOCRINE DISEASE: Steroidogenesis enzyme inhibitors in Cushing's syndrome

Daniel

Newell‐Price

2015

European Journal of Endocrinology

111

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Steroidogenesis enzyme inhibitors are the mainstay of medical therapy in Cushing's syndrome (CS). Ketoconazole (KTZ) and metyrapone are the most commonly used agents. Although there is considerable experience of their use in individual specialist centres, these drugs have not been rigorously tested in prospective clinical trials. Clinicians face uncertainties and concerns with respect to the safety profile of these agents, and best means to monitor effect. We review steroidogenesis inhibitors in the management of CS, including older agents (KTZ, metyrapone, etomidate and mitotane) and those currently under development (LCI699, non-racemic KTZ), and offer a practical approach for their use in clinical practice.

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Section: Etomidatementioning

confidence: 99%

Section: Etomidatementioning

confidence: 99%

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THERAPY OF ENDOCRINE DISEASE: Steroidogenesis enzyme inhibitors in Cushing's syndrome

Daniel

Newell‐Price

2015

European Journal of Endocrinology

111

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“…S(Ϫ)-etomidate was synthesized according to previously described procedures (20) with minor modifications. For all experiments, S(Ϫ)-etomidate solutions were made up using a stock solution of 2 mg ml Ϫ1 in 35% propylene glycol.…”

Section: Solutions-r(ϩ)-etomidate Was Obtained As Hypnomidate (2 Mg MLmentioning

confidence: 99%

Identification of Anesthetic Binding Sites on Human Serum Albumin Using a Novel Etomidate Photolabel

Bright¹,

Adham²,

Lemaire³

et al. 2007

Journal of Biological Chemistry

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We have synthesized a novel analog of the general anesthetic etomidate in which the ethoxy group has been replaced by an azide group, and which can be used as a photolabel to identify etomidate binding sites. This acyl azide analog is a potent general anesthetic in both rats and tadpoles and, as with etomidate, is stereoselective in its actions, with the R(؉) enantiomer being significantly more potent than the S(؊) enantiomer. Its effects on ␣1␤2␥2s GABA A receptors expressed in HEK-293 cells are virtually indistinguishable from the parent compound etomidate, showing stereoselective potentiation of GABA-induced currents, as well as direct mimetic effects at higher concentrations. In addition, a point mutation (␤2 N265M), which is known to attenuate the potentiating actions of etomidate, also blocks the effects of the acyl azide analog. We have investigated the utility of the analog to identify etomidate binding sites by using it to photolabel human serum albumin, a protein that binds ϳ75% of etomidate in human plasma and which is thought to play a major role in its pharmacokinetics. Using HPLC/mass spectrometry we have identified two anesthetic binding sites on HSA. One site is the well-characterized drug binding site I, located in HSA subdomain IIA, and the second site is also an established drug binding site located in subdomain IIIB, which also binds propofol. The acyl azide etomidate may prove to be a useful new photolabel to identify anesthetic binding sites on the GABA A receptor or other putative targets.Although it is now widely accepted that general anesthetics exert their effects by binding directly to their protein targets (1-3), information on the precise molecular locations of these binding sites has been slow in coming. Most information has been derived from in vitro electrophysiological experiments in which putative anesthetic targets, ion channels, or receptors, are genetically modified. What this approach provides is information on the molecular determinants of anesthetic sensitivity, but it is usually impossible to tell whether these determinants represent portions of anesthetic binding sites or regions of the channel or receptor that are responsible for transducing anesthetic binding into changes in channel gating. In principle, the most direct approach would be to determine a high resolution crystal structure of the ion channel or receptor in question in the presence and absence of anesthetics. Unfortunately, because of the difficulties in crystallizing membrane proteins, such experiments are still some way off. An alternative strategy that has recently had some success is to use anesthetics that have been modified so that they contain photoactivatable groups. When these anesthetic analogs are illuminated with a bright light, they are converted into highly reactive intermediates, which then, hopefully, bind irreversibly to their targets.The idea of using photoaffinity labeling to identify anesthetic binding sites was first implemented using the volatile anesthetic halothane (4, 5). Halothane ...

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“…3). This is a unique short-acting nonbarbiturate hypnotic agent discovered in 1964 [95]. It is eliminated by ester hydrolysis in plasma and liver [96].…”

Section: Enzymatic Hydrolysismentioning

confidence: 99%

Retrometabolism‐Based Drug Design and Targeting

Bodor

Buchwald

2010

Burger's Medicinal Chemistry and Drug Discovery

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Retrometabolic drug design (RMDD) approaches are systematic methodologies aimed to design safe compounds with an improved therapeutic index. RMDDs thoroughly integrate structure– activity and structure‐metabolism considerations into the entire design process and incorporate two major concepts aimed to design soft drugs and chemical delivery systems, respectively. Soft drugs (SDs) are new, active therapeutic agents designed to undergo predictable metabolism resulting in inactive metabolites after exerting their desired therapeutic effect(s). Chemical delivery systems (CDSs) are biologically inert molecules that provide enhanced and targeted delivery of an active drug to a particular organ or site through a designed sequential metabolism that involves several steps. Here, we present a comprehensive review including a general overview of the RMDD principles and a large number of specific examples from various pharmacological areas, including many recent developments, to illustrate RMDD concepts. Whenever possible, the rationale for the design as well as the pharmacokinetic and pharmacodynamic properties of the new therapeutic agents are briefly summarized and compared to those of the other compounds used in the same field.

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DL-1-(1-Arylalkyl)imidazole-5-carboxylate Esters. A Novel Type of Hypnotic Agents

Cited by 79 publications

References 0 publications

THERAPY OF ENDOCRINE DISEASE: Steroidogenesis enzyme inhibitors in Cushing's syndrome

THERAPY OF ENDOCRINE DISEASE: Steroidogenesis enzyme inhibitors in Cushing's syndrome

Identification of Anesthetic Binding Sites on Human Serum Albumin Using a Novel Etomidate Photolabel

Retrometabolism‐Based Drug Design and Targeting

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