Soft drugs are specifically designed to be rapidly metabolized and thus short acting. A common design feature is the presence of an ester group that is highly susceptible to hydrolysis by esterases. 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
A key feature of all soft drugs is that their metabolic stabilities and durations of action must fall within an optimal range to be most clinically useful.7
A drug that is too rapidly metabolized and short acting will require the administration of impractically large quantities to maintain a therapeutic effect and may generate metabolite concentrations sufficient to produce undesirable side effects when given for a prolonged period of time.8
Conversely, a drug that is too slowly metabolized and long acting will have pharmacokinetic properties that are not meaningfully different from the metabolically stable “hard” drug from which it was derived. Unfortunately, design strategies for controlling the metabolism of soft drugs to optimize their durations of action and improve their clinical utilities are not well established.
We recently developed methoxycarbonyl etomidate as the prototypical member of a new class of “spacer-linked etomidate esters” to test the hypothesis that soft analogs of etomidate could be designed that produce hypnosis without prolonged adrenocortical suppression ().9
We showed that it is rapidly hydrolyzed in rat blood and human liver s9 fraction and produces hypnosis and adrenocortical suppression of extremely short duration when administered to rats as an intravenous bolus.8,9
Although rats typically hydrolyze ester-containing drugs faster than large animals, subsequent studies in sheep and dogs indicated that methoxycarbonyl etomidate’s duration of action is similar across species (verbal communication, John Randle, Ph.D., Annovation BioPharma, Inc., Cambridge, MA, October, 2011). This suggested that methoxycarbonyl etomidate would be too short acting for many clinical uses and led us to consider how its duration of action could be lengthened.
Structures of (A) etomidate and (B) spacer-linked etomidate esters. The number of CH2 groups in the spacer is n.
Previous studies have shown that esterase-catalyzed hydrolysis of ester moieties is hindered by nearby substituents that protect the ester by steric, electronic, inductive, or in the case of chiral substituents, by chiral effects.10,11
This led us to hypothesize that methoxycarbonyl etomidate’s hydrolysis rate could be attenuated and its duration of hypnotic action beneficially lengthened using this molecular design strategy. If this hypothesis were correct, we predicted that it would be possible to develop a family of spacer-linked etomidate esters with members having widely varying pharmacokinetic properties, allowing the identification of compounds with the most promising characteristics for further testing and development. More broadly, our work could provide a blueprint for tailoring the pharmacological properties of other soft drugs to achieve specific clinical needs. To test our hypothesis, we synthesized spacer-linked etomidate esters containing various aliphatic groups appended to the carbon spacer linking the labile ester moiety to the etomidate backbone. We then assessed the impact of these substituent groups on in vitro
metabolic stability in rat blood and in vivo
hypnotic potency and duration of action in rats.