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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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March 4, 2008

Off Target? Which Target Did You Mean?

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Posted by Derek

Here's a snapshot for you, to illustrate how little we know about what many of our compounds can do. I was browsing the latest issue of the British Journal of Pharmacology, which is one of many perfectly respectable journals in that field, and was struck by the table of contents.

Here, for example, is a paper on Celebrex (celecoxib), but not about its role in pain or inflammation. No, this one, from a group in Turin, is studying the drug's effects on a colon cancer cell line, and finding that it affects the ability of the cells to stick to surfaces. This appears to be driven by downregulation of adhesion proteins such as ICAM-1 and VCAM-1, and that seems to have nothing particular to do with COX-2 inhibition, which is, of course, the whole reason that Celebrex exists.

This is a story that's been going on for a few years now. There's been quite a bit of study on the use of COX-2 drugs in cancer (particularly colon cancer), but that was driven by their actual COX-2 effects. Now it's to the point that people are looking at close analogs of the drugs that don't have any COX-2 effects at all, but still seem to have promise in oncology. You never know.

Moving down the list of papers, there's this one, which studies a well-known model of diabetes in rats. Cardiovascular complications are among the worst features of chronic diabetes, so these folks are looking at the effect of vascular relaxing compounds to see if they might provide some therapeutic effect. And they found that giving these diabetic rats sildenafil, better known as Viagra, seems to have helped quite a bit. They suggest that smaller chronic doses might well be beneficial in human patients, which is definitely not something that the drug was targeted for, but could actually work.

And further down, here's another paper looking at a known drug. In this case, it's another piece of the puzzle about the effects of Acomplia (rimonabant), Sanofi-Aventis's one-time wonder drug candidate for obesity. It's become clear that it (and perhaps all CB-1 compounds) may also have effects on inflammation and the immune system, and these researchers confirm that with one subtype of blood cells. It appears that rimonabant is also a novel immune modulator, which is most definitely not one of the things it was envisioned as. Do the other CB-1 compounds (such as Merck's taranabant) have such effects? No one knows, but it wouldn't come as a complete surprise, would it?

These are not unusual examples. They just serve to show how little we understand about human physiology, and how important it is to study drugs in whole living systems. You might never learn about such things by studying the biochemical pathways in isolation, as valuable as that is in other contexts. But our context in the drug industry is the real world, with real human patients, and they're going to be surprising us for a long time to come. Good surprises, and bad ones, too.

Comments (8) + TrackBacks (0) | Category: Cardiovascular Disease | Diabetes and Obesity | Drug Development | Toxicology


COMMENTS

1. SP on March 4, 2008 11:33 AM writes...

The Viagra one is not surprising, the original target indications were hypertension and angina. The legend is that patients refused to return the remaining doses because they were pleased with certain side effects.

Permalink to Comment

2. sroy on March 4, 2008 2:24 PM writes...

Just a few comments.

Data obtained at supra-physiological drug concentrations in any cell lines is suspect. While such data might be a good starting for a very fruitful project, the converse is very often true. For example genestein (soya bean) has been shown to be a tyrosine kinase inhibitor, a partial estrogen agonist, an anti-oxidant and inhibitor of many other signal transduction proteins/kinases.

However we are still not sure if it is the reason behind asian women (in asian countries) having much lower rates of breast cancer than women of european ancestry. Because even asian women who eat western diets still have a lower rate of breast cancer than women of european ancestry.

About PDE5 inhibitors and vascular dysfunction. As a previous poster has mentioned, this could have been expected. NO mediated smooth muscle signaling (cGMP increases) also seems to reduce the effect of age on vascular histology (elasticity vs rigidity) and maintains endothelial function (feedback loops?)

At the risk of sounding like a shill for viagra (or other PDE5 inhibitors), I think that taking small doses (lower end of dosage) of these compounds on a regular basis by middle aged men might reduce their future risk (10-20 years on) of severe ED. They certainly help speed up the extent and speed of functional recovery in younger men (below 55) who have undergone radical prostatectomy. It is possible that the same effect would also slow down the progress of age related ED. Even if it does do that in a given person, it is unlikely to speed up the disease process. A million naproxen prescriptions will put more people in hospital (GI bleeds) than a million Viagra prescriptions- and naproxen is OTC.

About rimonabant- It seems that it did start multiple sclerosis in one woman in a clinical trial. The MS went into an almost complete remission a couple of months after she stopped talking it. Given that many MS patients have reported for more than a few years that THC improves their symptoms, the converse was always a possibility with an antagonist (or inverse agonist) in predisposed human beings.

Permalink to Comment

3. emjeff on March 4, 2008 3:02 PM writes...

The notion that CB-1 antagonists might have off-target effects responsible for their AE profiles is interesting on two fronts. First, it is interesting pharmacology. More interesting to me, though is the likelihood that CB-1 agonists (e.g. marijuana)have off-target effects. We won't hear from the "medical marijuana" crowd on this, I'll bet.

Permalink to Comment

4. Jonadab on March 4, 2008 6:04 PM writes...

Oh, man, that second one pretty much writes its own jokes, doesn't it?

Permalink to Comment

5. bob on March 4, 2008 6:47 PM writes...

I think this just serves to illustrate the problems/dangers with the current model of drug discovery. When you search for a small molecule that affects your target, then make sure it doesn't cause any obvious problems anywhere else, you certainly leave a whole lot of room for binding to other things and causing subtle effects. There's a reason nature didn't try to come up with a small molecule signal for everything.

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6. NJBiologist on March 4, 2008 6:55 PM writes...

I used to work for a guy who said there were only two questions in drug development: does it work, and is it safe. It felt a little anti-intellectual, and it's not conducive to finding follow-on compounds, but I'm starting to believe the old guy.

Permalink to Comment

7. Petros on March 5, 2008 5:20 AM writes...

Further to the comments on Viagra, Sufrace Logix is developing SLX-2101 an ultra long acting PDE5 inhibitor for the treatment of major cardiovascualr conditions.

And on another track there are a number of companies that have sought to focus on ddeveloping old drugs for new indications as a low risk stratgey for drug development

Permalink to Comment

8. tom bartlett on March 5, 2008 8:53 AM writes...

Colon cancer via ICAM inhibition, eh? Well maybe those alarmists who believe COX-2 inhibitors are bad would be willing to suspend judgement on, say, a 0% BA polymer-bound Celebrex, or something of that sort.

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