Tweaking A Workhorse Anesthetic
Aug22

Tweaking A Workhorse Anesthetic

In this week’s issue of C&EN, I’ve written about the search for new anesthetic drugs, as well as the accompanying quest for a better understanding of how anesthetics work. Anesthesia is safer than it’s ever been because highly trained physicians and nurses can manage its complications. The drive to improve anesthetics is nowhere near as strong as it is for other drug classes such as oncology drugs, as Imperial College biophysicist Nick Franks told me. But that doesn’t mean the drugs in use are perfect. Take propofol, or 2,6-diisopropylphenol, which is marketed as Diprivan by AstraZeneca. It’s arguably the most commonly used injectable anesthetic for surgeries in developed nations. It even has a nickname around the operating room, “milk of amnesia”, because of its effects on memory, and because of the milky appearance the sparingly water soluble compound takes on in the oil-water emulsion needed to deliver it to the bloodstream. But propofol has side effects. Several firms have made adjustments to propofol or its formulation in order to address the limitations, and they’re finding out whether those chemical tweaks translate into benefits for patients. For example, researchers at PharmacoFore, a privately-held biopharmaceutical company in San Carlos, Calif., reasoned that small changes to propofol’s structure might cut down on the pain experienced when propofol is injected. Anesthesiologists often use a topical numbing agent such as lidocaine to alleviate this pain. Work from other researchers suggested that the low concentration of propofol in the aqueous phase of the oil-water emulsion acts directly on a receptor on the inside of blood vessel walls to cause pain, says Thomas E. Jenkins, PharmacoFore’s chief scientific officer. “Short and sweet, our strategy was to make propofol more lipophilic,” in order to further reduce the concentration of the drug in the aqueous phase, the portion thought to be responsible for the pain, Jenkins says. PharmacoFore’s chemists also tried to leverage the concept that a single stereoisomer of a molecule can have pharmacological properties different from those of a mixture of stereoisomers. They investigated specific stereoisomers of 2,6-di-sec-butylphenol, which is more hydrophobic than propofol. The racemic version of this compound was similar enough to propofol that it hadn’t escaped chemists’ notice in the past- its anesthetic properties were evaluated in the 1980’s by the company that developed propofol itself (J. Med. Chem., DOI: 10.1021/jm00186a013). PharmacoFore evaluated a specific stereoisomer, (R, R)-2,6-di-sec-butylphenol (PF0713), in a phase I clinical study. In that study, PF0713 rapidly induced general anesthesia without injection pain and with minimal drop in blood pressure (blood pressure lowering is another known side effect of propofol). In addition, data from a preclinical study in rats combined...

Read More