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...

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Finding Out Anesthetics’ Mode Of Action
Apr28

Finding Out Anesthetics’ Mode Of Action

When I think about how drug discovery has changed in the last 100 years, one of the first things that comes to mind is how much more target-focused the process is. Take aspirin as an example of the earlier model. Researchers didn't confirm how aspirin worked until John Vane's landmark 1971 paper, over 70 years since aspirin first hit the market. Compare that to today's world of drugmaking, where oftentimes researchers have to validate a target- show that it is connected to a disease and that modifying its activity might help treat that disease- before drug discovery can really get going. We've written about this process many times- see this account of the development of Lexicon drug candidate LX1031 for irritable bowel syndrome as an example. But there's at least one class of drugs where this target-based philosophy is in its infancy- anesthetic drugs. That's because researchers are only beginning to understand the molecular basis of anesthesia. So it's not clear which proteins to target or even whether you'd want a molecule that's selective for one target. The New York Times spoke with Harvard anesthesiologist Emery Brown last month about the neurobiology of anesthesia, and how being under actually is more like a coma than going to sleep. Other researchers are trying to understand anesthesia at the molecular level, like chemists Ivan Dmochowski and Bill Dailey, and anesthesiologist Rod Eckenhoff of the University of Pennsylvania. I visited their labs yesterday on a jaunt to Philadelphia. They're among a small number of research teams building fluorescent or light-reactive versions of the anesthetics used in hospitals every day*, in order to figure out what proteins they interact with and which of those are relevant to inducing anesthesia. They've got their work cut out for them- for one thing, the anesthetics that are administered by inhalation, such as isoflurane and sevoflurane, bind to a slew of proteins. But if their efforts pay off, they say they will eventually be able to help chemists build better, safer anesthetics. More reading: Molecular targets underlying general anesthesia, NP Franks, Br. J. Pharmacol. 2006, 147, S72. *by anesthesiologists like the guy I married, in the interest of full...

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