Anesthetic drug development: Novel drugs and new approaches

Abstract

The ideal sedative-hypnotic drug would be a rapidly titratable intravenous agent with a high therapeutic index and minimal side effects. The current efforts to develop such agents are primarily focused on modifying the structures of existing drugs to improve their pharmacodynamic and pharmacokinetic properties. Drugs currently under development using this rational design approach include analogues of midazolam, propofol, and etomidate, such as remimazolam, PF0713, and cyclopropyl methoxycarbonyl-etomidate (MOC-etomidate), respectively. An alternative approach involves the rapid screening of large libraries of molecules for activity in structural or phenotypic assays that approximate anesthetic and target receptor interactions. Such high-throughput screening offers the potential for identifying completely novel classes of drugs. Anesthetic drug development is experiencing a resurgence of interest because there are new demands on our clinical practice that can be met, at least in part, with better agents. The goal of this review is to provide the reader with a glimpse of the novel anesthetic drugs and new developmental approaches that lie on the horizon.

Keywords: Anesthetic; etomidate; midazolam; propofol.

Figure 1

Structures of midazolam and propofol

Figure 2

Remimazolam is a benzodiazepine that contains a metabolically labile ester moiety that renders it ultra-short acting. JM-1232(-) is a benzodiazepine-like sedative–hypnotic with a very high therapeutic index

Figure 3

Methoxycarbonyl-etomidate (MOC-etomidate) is a rapidly metabolized etomidate analogue. Cyclopropyl MOC-etomidate is a more potent and longer-acting analogue of MOC-etomidate. Carboetomidate is a pyrrole etomidate analogue. MOC-carboetomidate has structural and pharmacologic properties present individually in MOC-etomidate and carboetomidate

Figure 4

PFO713 is a propofol analogue that causes less pain on injection than propofol. AZD-3043 is a propanidid analogue, differing only by the presence of an additional methylene group and formulated as an emulsion

Figure 5

Positive control performance in 1536-well format in quantitative high-throughput screening mode. Each curve is a titration of the 1-AMA/apoferritin mixture with propofol from 7 to 150 μM from each of the 1509 separate plates. The average IC₅₀ = 23 μM and MSR of 3.3

Figure 6

A 3D plot of the active group from the full screen. This set of curves represents about 7%, or almost 25,000 of compounds that showed inhibition of the 1-AMA fluorescence. The green curves are the positive controls (propofol), and the light blue are those that showed weak inhibition. The “top actives,” or those that inhibited greater than 60%, are the dark blue group, representing about 2500 compounds

Figure 7

Concentration effect curves from the quantitative high-throughput screening run of a group of top-active compounds clustered on chemotype. Despite showing greater than 10-fold differences in potency, note compounds in this cluster inhibited greater than 60%, suggesting that further attention be devoted to this chemotype