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 with established data on propofol anesthetic potency suggested that PF0713 had greater anesthetic potency compared to propofol.

Other companies have tried the opposite strategy– making water-soluble versions of propofol to address some of propofol’s other disadvantages, explains Mariusz Banaszczyk, senior manager of R&D chemistry at Alere in San Diego. Banaszczyk helped to develop water-soluble propofol drug candidates while working at the Immune Response Corporation during the late 1990’s, in collaboration with La Jolla-based Vyrex Corporation. Propofol’s lipid formulation causes allergic reactions in some patients, Banaszczyk says. It also fosters microbial growth, so unused portions of an opened bottle of propofol must be discarded within a matter of hours.

The team Banaszczyk joined was making water soluble propofol prodrugs which enzymes in the body could convert to propofol itself. “When I joined the project the idea was to make a hemisuccinate monoester at propofol’s hydroxyl group,” he says. “But those compounds were not stable enough to provide a long shelf life.” So the chemistry team switched to phosphate prodrugs, which proved more shelf-stable. Banaszczyk left the Immune Response Corporation in 2003.

In 2008, the Food and Drug Administration approved a propofol prodrug from Eisai, known as Lusedra (fospropofol). It is approved for moderate sedation, not the more profound sedation needed for general anesthesia.

“I don’t think any propofol prodrug will entirely replace propofol,” Banaszczyk says. Because the body must metabolize prodrugs to their active form, prodrugs lack propofol’s rapid onset of action. They also require longer recovery times. “If surgeons and anesthesiologists want fast on and off rates, then no prodrug will be able to meet propofol’s performance.” Still, prodrugs’ different properties could prove to be assets for medical applications outside of general surgery, such as in sedatives for diagnostic procedures, he says.

Author: Carmen Drahl

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3 Comments

  1. Seems like hydrolysis of that prodrug will produce formaldehyde; tolerable but probably not ideal if you can avoid it. I wonder if connecting the phosphorus directly to the phenolic oxygen will work.

  2. Carmen, a very nice “teaser” post to go to your truly terrific article on anesthetics development and target elucidation. I used to teach anesthetics as part of my CNS pharmacology section and this article would be an excellent assignment for my students (are you listening pharmacology prof in medical, pharmacy, dental, and nursing schools???)

    Regarding the low therapeutic index of anesthetics, I used to remark that it’s amazing that we’ve been so successful in developing safe agents where the desired therapeutic effect is to bring you halfway to death (on the spectrum of sedation->hypnosis->anesthesia->coma->death).

    Also, hearty congratulations for having your article picked up in yesterday’s e-newsletter of the Foundation for Biomedical Research – it must’ve been due to your mention of Eckenhoff’s tadpole anesthesia bioassay.

    You’re an excellent chemist but we’re making a pretty good pharmacologist out of you!

  3. I’m amused that PharmacoFore is using the same “PF” code as a much larger company.

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