Structural Modification in Anesthetic Drug Development for Prodrugs and Soft Drugs

Abstract

Among the advancements in drug structural modifications, the increased focus on drug metabolic and pharmacokinetic properties in the anesthetic drug design process has led to significant developments. Drug metabolism also plays a key role in optimizing the pharmacokinetics, pharmacodynamics, and safety of drug molecules. Thus, in the field of anesthesiology, the applications of pharmacokinetic strategies are discussed in the context of sedatives, analgesics, and muscle relaxants. In this review, we summarize two approaches for structural optimization to develop anesthetic drugs, by designing prodrugs and soft drugs. Drugs that both failed and succeeded during the developmental stage are highlighted to illustrate how drug metabolism and pharmacokinetic optimization strategies may help improve their physical and chemical properties.

The use of prodrugs as drugs of abuse

“…Prodrugs of benzodiazepines have potential therapeutic applications even with a more complicated metabolic pathway (Deng et al, 2022). They can also, however, appear in the illicit drug market and may receive the denomination "designer benzodiazepines."…”

“…Prodrugs of benzodiazepines have potential therapeutic applications even with a more complicated metabolic pathway (Deng et al, 2022). They can also, however, appear in the illicit drug market and may receive the denomination “designer benzodiazepines.” Designer benzodiazepines are a growing class of new psychoactive substances, based on modifications of legally available benzodiazepines, pharmaceutical candidates that have not been approved for medical use, active metabolites of approved drugs and synthesis of triazolo‐analogues of 1,4‐benzodiazepines (Wilde et al, 2021; Zawilska & Wojcieszak, 2019).…”

“…Prodrugs can be defined as active principles which are inactive when administered, but through interaction with enzymes and the metabolic environment of different tissues are degraded into the drug with potential to interact with the different receptors (Elliott et al, 2020; Rautio et al, 2008). They are frequently developed with an easily removable labile group (such as an ester) to allow quick and thorough conversion in tissues or in the gastrointestinal tract (Deng et al, 2022; Rautio et al, 2018).…”

Anesthetic drug discovery with computer-aided drug design and machine learning

“…Different from de novo drug design, there are two typical approaches to designing new drugs based on existing drug molecules. One is to screen new compounds from derivatives of FDA-approved drugs [205]. In a recent study, Azamatov et al introduced computational AMDET prediction methods to develop novel local anesthetics with lower toxicity.…”