PF-0713

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.

Although well established in clinical practice, both propofol and midazolam have limitations. New hypnotics with different and potentially superior pharmacokinetics and pharmacodynamics are under development. These include the benzodiazepine receptor agonists CNS7056 and JM-1232 (-), the etomidate-based methoxycarbonyl-etomidate and carboetomidate, the propofol-related structures PF0713 and fospropofol, and THRX-918661/AZD3043. The basic pharmacology and the initial anaesthesia studies for each of these agents are reviewed. Several of the agents (CNS7056, THRX-918661/AZD3043, and fospropofol) have reached the stage of clinical trials. To be successful, novel compounds need to establish clear clinical advantages over existing agents and where possible the new agents are discussed in this context. Computer-controlled drug administration offers the ability to automatically implement infusion schemes too complex for manual use and the possibility of linking patient monitoring to administration to enhance patient safety.