April 24, 2007

Potential new treatment for HIV

The first truly new treatment for HIV to come along in a while has just passed over another hurdle.  The FDA antiviral advisory panel has backed the approval of Pfizer’s CCR5 inhibitor Maraviroc.  This compound is unique from currently approved HIV-inhibitors since it targets a host-receptor, CCR5, and prevents the virus from using this receptor as a handle with which to gain access to the cell. The discovery of CCR5 as a potential drug target is just as compelling as the discovery of the drug which was developed by Pfizer to exploit this point in the virus’ replication cycle.

Early on in the AIDS crisis it was realized that certain individuals appeared to be resistant to infection with HIV while at the same time another set of patients showed little disease progression after they were infected. The explanation for these phenomena came when it was discovered that the virus needed the host cell receptor CCR5 in addition to the CD4 receptor to bind to and gain entry into the cell. Those individuals who were resistant to infection as well as those who were non-progressors possessed a mutant form of the CCR5 gene which reduced its expression. Resistance to infection occurrs for homozygous individuals while slow disease progression occurs in those who are heterozygous. Moreover, in the general population people who carry this mutation appear to be perfectly healthy which immediately indicated that it might be a useful target. Researchers in the field called this an “experiment of nature” since nature had essentially carried out a gene knock-out experiment.

 

Word of the week…Placebo 

In the strictest definition it the measured response to an inactive substance brought about solely by the patient’s belief that it will work in a prescribed manner…ie. the “power of suggestion” and the patient believing they will respond according to the suggestion is all that is needed to elicit a response.

Double-blind, placebo controlled drug trials are now considered the gold standard by which a drug’s safety and effectiveness is measured. In order for a drug to be considered useful and safe it must demonstrate increased efficacy or response rate compared to placebo while at the same time show a reduced incidence or degree of side effects. In recent years there has been some debate on whether the use of placebo provides the fairest comparison of a new drug particularly in areas where a treatment already exists.

However, a more basic question one might ask is whether there really is such a thing as a placebo effect according to the definition above. Granted, responses to placebo treatment have been reported and in certain cases patients treated with an inactive substance how shown response rates up to 30%. But are these true object responses that can measured by unbiased clinical observations or are these so-called responses just artifacts of the subjective determination the outcome? My belief is that there is probably not some special phenomenon behind the placebo response and that people can not effect a physical response to an inactive substance through the power of suggestion.

At the extreme end of the spectrum the existence of a true placebo response is easy to argue against. Clinical trials that lean on the patients self-evaluation of their symptoms to determine their response to a drug will most likely be influenced by the subjective nature of the outcomes measurement. Typically these are clinical trials of drugs such as anti-depressants, anxiolytics and in some cases pain medications and not surprisingly these trails are accompanied by high “response rates” to placebo treatment.

To be fair, there are trials were measurable objective responses have been seen, but the question still remains about whether this true placebo response. It is in cases that the response is the result of some unaccounted for factor inherent in the trial design, for some patients the clinical setting alone might be responsible for the response…patients might be eating better, sleeping better or be more relaxed.

To get at the answer to this question a group in Copenhagen has reviewed a number of clinical trials (New England J. Med. (2001) 344, 1594 (no DOI), J. Internal Med. (2004) 256, 91)  Most importantly, they have looked only at clinical trials which included a “no treatment” arm in addition to the placebo arm with the idea being that this would show whether there was a true placebo response. The result was that they found little evidence that patients treated with placebo faired better than patients who received no treatment, except for trials that looked at medications for pain, but given the subjective element in this type of trial it is not surprising.

April 14, 2007

These are a little overdue… 

Word(s) of the week…Stem cells 

Here in the US Stem Cells have been in the headlines lately. Not the science of stem cells but the politics of stem cells and we in the pharma community have had front row seats on the debate.

On the right, we have politicos such as George Bush and the religious-right who take the position that human embryonic stem cells should be considered “human life” and manipulating these cells for the sake of knowledge violates the “sanctity” of life.  Furthermore, using the ’slippery slope’ argument the religious groups fear that any use of tissue obtained from abortions would in effect perpetuate the procedure by making it a ‘nessicity’. Therefore, under the current administration the federal government is prohibited from funding stem cell research.

On the other side, we have scientists and patient rights advocates who scoff at the notion that stem cells should be considered “sacred” and view their opponents as being overzealous and major obstacles to the potential treatments of a number of debilitating diseases.

In my opinion, I think both sides are guilty of manipulating the truth to make their point, but being a scientist I am most concerned with the message being put forth by those in favor of stem cell research..I believe we have gone too far in exalting the potential of stems cells to provide cures for such a wide number of diseases in such a short time frame. While I am still young, I have been in the pharma field long enough to know hype when I see it. In my opinion any potential therapy involving stem cells will be decades away if not longer and will likely be successful for only a small set of diseases…Just look how long it took for monoclonal antibodies to make it onto the market…almost 30 years after Kholer and Milstein discovered how to make them. While I am thinking of it…how long have we been working on gene therapy??

Another issue surrounding stem cells that is often not discussed is cost…stem cell therapy will not be cheap by any stretch of the imagination. This is especially relevant considering that most governments have become very cost conscious when it comes to health and the US is on the verge of implementing cost controls on health care…(I won’t talk about the irony of the fact that the politicians who are pushing for stem cell research are the same ones that are behind the cost control legislation)…I expect that the price tag for a typical treatment could be anywhere from $50,000 to $500,000, and with this large price how could we afford to treat conditions such as Parkinsons or Alzheimers which afflict such a large number of people.

Hats off to Paul Knochel

Long before Phil Baran (a brilliant chemist indeed) was promoting protecting-groupless synthesis Paul Knochel and other were challenging people’s assumptions regarding the need for protecting groups in Grignard and Zinc-metallate mediated reactions.  A nice little paper in SynLett shows how to generate Grignard or Zincate of imidazole without the need for protecting groups. The trick here is the use of LiCl which aids the solubility of the reactants and reagents and increases their reactivity. Knochel doesn’t cite it but the current application of LiCl is reminiscent of Seebach’s work use of this salt to increase the solubility of cyclosporin in THF.

Word of the week…Randomness

I know I am treading in unfamiliar territory (at least to me) on this one…but it has been something that has been puzzleing me for some time.

In the observable universe, an event which has more than one outcome (eg. a coin toss) is random if the probability of the outcomes are equal. Basically I would agree with this, however the thing that puzzless me, is the assumption that there can be an event where more than one outcome is equally probable.

Going back to the coin toss for example, on any given toss the chances that the coin will land heads- or tails-up is determined by a number of variables…how many times the coin flips, the number of bounces it takes when it hits the ground, etc… If one could reproduce these variables (and people have been able to do it) the coin would land the same side up every time, ie. the outcome of the toss is not completely random it is predetermined by the “path” the coin takes before coming to rest on the ground. The coin toss only “appears” to be random since there are a large number of uncontrollable variables.

This leads to me to wonder about the whoel concept of randomness. Is there anything truley random in the observable universe, or do things just appear to be random?

Tamiflu

Tamiflu, the anti-influenza neuraminidase inhibitor, discovered by Gilead and marketed by Roche has been taking a beating lately. In Japan over 1000 adverse events have been reported in the less than 6 years since the time it became available. The interesting thing is that 128 of these reports suggest some type of CNS toxicity mainly involving apparent highly reckless behaviour…attempting to jump off buildings or running in front of moving cars.

In addition, Tamiflu-resistant virus is popping up, even in people who have never taken the drug. At this point it doesn’t appear to be a problem, since most people can handle the flu, regardless of its resistance profile to this drug. The real danger would be if this scenario repeats itself during an outbreak of a more lethal strain, such as the H5N1 virus. Nonetheless, it’s likely that this situation can be reversed if doctors and patients are more vigilant in prescribing and taking the drug, respectively.

With regards to the side effect issue, it would be interesting to see if Glaxo’s neuramindiase inhibitor Zanamir, causes the same problems. I suspect it won’t since unlike Tamiflu, which is an oral drug, Zanamivir is poorly absorbed and thus must be given by inhalation where only 4 to 17% of the drug is systemically absorbed. When talking about treating the flu, this is fine because the virus is located in the respiratory tract. Therefore, if it turns our that the Tamiflu side-effects are caused by the drug and that they are related to the drug’s mechanism, Zanamivir could offer a safer alternative since there would be less systemic exposure.

Uncanny resemblance

I recieved the first news letter from the European Federation of Medicinal Chemistry (EFMC)….Its interesting, but what really hit me was the uncanny resemblance of the president, Roberto Pelliacciari, to Steve Martin’s character in the 2003 movie, Looney Tunes Back in Action.

Steve Martin

Word of the week…Racemate

The definition of racemate, an equimolar mixture of enantiomers, is old hat to most of us having learned it in our introductory organic chemistry courses. And so it was for me until recently.

Being a synthetic chemist, I don’t have much time or energy to gain a deep understanding of physicochemical properties. Therefore, I was not surprised to find that I was ignorant of the fact that in the solid state racemates come in two flavors and that the IUPAC has developed specefic nomenclature to define each. There is a “racemic compound” where the two enantiomers are co-crystallized homogenously into a single crystal. However, racemates can also exist as “racemic conglomerates” which describes the situation where the two enantiomers crystallize separately but still might be occluded in a single particle.

Tangentially related to this topic is Wallach’s rule which states that racemic crystals (ie. racemic compounds) are more dense than the crystals of the pure enantiomers. Which makes me think…since increased crystalline density is generally associated with increased stability and increased crystalline stability can be correlated with reduced aqueous solubility, one would expect that racemates would be less soluble than their pure enantiomers. I did a search of the literature see if this was the case and come up with the examples below..there appears to be a  slight trend.

Intermolecular ene reaction

This a little overdue…Some interesting chemistry reported in Journal of the American Chemical Society….Interesting not for the products that it produces but for the proposed mechanism, an intermolecular ene-reaction. From a retrosynthetic point of view one can imagine that the product of thisreaction could also be formed just as easily from the corresponding aldehyde via and Aldol reaction instead. However, the authors provide evidence to show that the reactants, as their enols, go through an ene-type process.

Given that this reaction occurs at room temperature simply by mixing the two substrates together is also noteworthy and makes me wonder why nobody had reported this before.

Spit on this chip and call me in the morning….

Home-based diagnostics could potentially become more widespread, allowing people to get a quick heads-up on the presence of disease while at the same time, allowing doctors to prioritize these patients accordingly. For example, we currently have home pregnancy tests which have proven to be very useful for family planning etc…

In the future, the priniciple of using simple tests that people could use at home if they are concerned about the presence of a certain disease could become more wide spread. Depending on the outcome of the test their family physician would more quickly and more efficiently be able to direct them to the appropriate avenue of follow-up.

An interesting paper in the Proceedings of the National Academy of Sciences, USA, suggests that we might be close to realizing this goal. Using a small cartridge capable of “working up” saliva and carrying out a small scale-immunoassay, researchers were able to assay for the presence of MMP-8 (matrix metalloproteinase a protein biomarker of periodontal disease. However, this assay has the potential to provide early diagnosis for a number of diseases beyond the immediate application for detecting periodontitis since there is an established link between periodontal disease and other malladies such as cardiovascular and pulmanary disease as well as the increased risk of premature birth.

Superstitious

Being a synthetic chemist, I have developed a cetain amount of superstition and am always concerned about angering the ‘gods’ of sucess. One thing that I have learned is that nothing puts a jinx on a program more than winning an award. And so it would appear with Pfizer’s Zyvox (linezolid), originally developed by Upjohn prior to the subsequent mergers with Pharmacia and Pfizer.

It seems that in a recent phase III trial where it was tested for its ability to prevent catheter-related infections it actually increased the risk of death and as such the trial has been halted.

The funny thing is, that the team which discovered Zyvox was recently honored by the ACS for this achievement while at the same time the Pharmaceutical Researchers and Manufacturers of America PhRMA) handed out a Clinical Trial Exceptional Servic Award to two researchers involved in the clinical development of the compound….coincidence???

Synthesis of indolizines, pyrrolones and indolizinones

Simple heterocycles are the work-horse of modern medicinal chemistry, but unfortunately they don’t get as much attention, at least in academia, as more sterochemically complex molecules. I have had many instances where I needed to make a certain heterocyclic target but found that there was very little, if any, literature precedent concerning the heterocycle I was interested in. It is refreshing to find academic types developing new methods for the synthesis of heterocylic systems.

An interesting paper in Org. Lett. from the Sarpong group at UC Berkeley involves a simple method for the synthesis of pyridine fused heterocycles starting from readily available starting materials. The key step in the method involves a Pt(II) catalyzed ring closure which subsequently undergoes proton transfer and/or rearrangement to provide 5 or 8, depending on the subtituent attached to the carbinol center.