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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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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« November Conference on Drug Discovery in Boston | Main | Crowdfunding A CNS Project »

October 5, 2012

The Return of CB1

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Posted by Derek

CB1 ligands were all the rage a few years ago, headlined by Sanofi's rimonabant. These looked like the best shot at the obesity market in a long time, if you were of an optimistic frame of mind. But the entire class came crashing down with the regulatory rejection of rimonabant itself, followed by the failure of Merck's taranabant in the same area. (Pfizer publicly dropped out of the area, and number of other CB1 programs never even upped periscope, after watching the chaos up there on the surface).

Now there might be another shot. CNS side effects doomed the original ligands, but many people thought that the brain was the site of action. How about a compound that's selective for the periphery? Work has been going on over the last few years to just that end, It turns out that these actually do seem to show effects in rodent models, so the chase might be on again. You'd think that anything that avoids the brain, with its ever-present potential for "Wow, who knew that would happen?" effects, would have a better shot. Given the size of the obesity market, I think we'll be given the chance to find out. . .

Comments (10) + TrackBacks (0) | Category: Diabetes and Obesity


COMMENTS

1. Virgil on October 5, 2012 8:28 AM writes...

For most people I know in the obesity field, the failure of rimonabant is viewed as the FDA's darkest hour. The phrase "patients are morbidly obese, of course they're suicidal" got thrown around a lot, and I'm inclined to agree with that assessment. 5 years later and we're still lacking good obesity drugs (Qnexa doesn't even come close in efficacy).

Maybe they can couple rimonabant to that beautiful molecule you blogged about yesterday? (http://pipeline.corante.com/archives/2012/10/03/a_lovely_petite_compound.php) Surely that would stop it crossing the BBB?

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2. Eve on October 5, 2012 8:33 AM writes...

>> Given the size of the obesity market

I see what you did there.

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3. NoDrugsNoJobs on October 5, 2012 9:29 AM writes...

#1 Virgil, I would have agreed with you but later, European authorities actually pulled rimonabant from the market because their real world experience with the drug was fraught with undesiraeable CNS side effects. Rimonabant is an inverse agonist with a very long half life. I think the problem could be that it actually cancels the endogenous encocannabinoid signaling and for those patients very sensitive to this effect, the risk is multiplied by the fact that even after the drug is stopped, it will stay in the system a long time. While this is only anecdotal, I know a European who had taken this drug. To me the person was quite stable, had a good job, education, etc and told me the drug really put him in a bad place, somehow it made him feel very melancholic and hopeless. He stopped taking the drug and eventually returned to his normal self. When one thinks of how some people "use" cannabis/pot/THC for pleasure and relief of anxiety and so on, it does seem logical that an inverse agonist could take people to a sort of opposite place that is less than pleasant. I think the real world signal was just way too strong to ignore. Now having said all this, perhaps it could have been left on the market and its use carefully monitored to minimize the possibility of serious adverse effects - I don't know. I agree that the efficacy were pretty impressive. It kind of makes me wonder whether a partial cannabinoid agonist would work for treating certain types of depression or melancholia....maybe some folks have inherently insufficient endocannabinoid signaling to maintain a "normal" mood. Obviously it couldn't be so strong that the person got high like from THC but more like a very low efficacy stimulation that would bring a person up to a more normal line. Just saying......

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4. Chemist turned Hedgie on October 5, 2012 9:45 AM writes...

#1 Virgil- what always scared me about rimonabant was the following line from FDA presentation at the AdCom:

"1308 healthy subjects from 37 completed Phase 1 studies"

By contrast, only 1230 were in P2 studies. That must surely be a world record for a pahse 1 program. We know it started out as a schizophrenia drug, but where else was it tried before it landed in obesity?

Dirty molecule doesn't come close to describing rimonabant...

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5. luysii on October 5, 2012 10:47 AM writes...

The CNS side effects of endocannabinoid mimics or antagonists can be traced to the structure of the endocannabinoids themselves. Look at the most abundant endocannabinoid -- e.g. 2-arachidonyl glycerol -- a nice hydrophobic compound with 19 carbons in a chain without nary a hydrophilic group. It's unlikely that the 2 hydroxyls of glycerol left standing can make it hydrophilic. Since the brain is mostly fat, drugs similar enough to bind to CB1 are likely to persist and persist.

Think of the potheads you've known. They were consistently dopey whether or not they'd actually been smoking recently. Any physician who's taken care of post-op patients receiving a lipid soluble general anesthetic knows they're not normal for days. While it's hard to distinguish this from the metabolic response to trauma, it takes lipid soluble drugs a long time to wash out from the brain.

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6. David P on October 5, 2012 11:56 AM writes...

Personally I am just excited that some of my coworkers got mentioned on In the Pipeline. :)

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7. milkshake on October 5, 2012 12:35 PM writes...

few carboxy and sulfonamide groups (just like in the awful drug here few days ago) or even pieces like triazoles will surely turn a molecule brain-nonpermeable.

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8. metaphysician on October 6, 2012 9:00 AM writes...

Do we actually know whether or not hunger-response is primarily regulated in the brain or the periphery, at least as far as a CB1 antagonist would be concerned? Because it seems logical to me that if hunger is primarily regulated in the brain, a variant molecule that doesn't penetrate the BBB is just going to fail to do anything.

( Yes, yes, some rat results. For these purposes, obesity is a neurological condition, which is to say, I'll believe studies when they happen in humans, no earlier. )

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9. In Vivo Veritas on October 8, 2012 10:46 AM writes...

I'm no chemist, but I bet a few of you here are...... the folks pushing the peripheral CB1 story have gone to lengths to show that their compounds do not enter the brain, but I'd say that nearly all of them have at least the potential for an (active?) metabolite which enters the brain. Do you chemists agree?

Given the low % of subjects who saw a CNS side-effect with rimonabant, how any patients do you think we'll need to dose before we see of these metabolites have CNS effects?

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10. DrDSW4 on October 10, 2012 2:02 PM writes...

I was in a 2 year double blind rimonbant obesity study. The drug was efective in year one as I lost over 65 pounds. In the second year, by week 3, it was evident that I was changed to the placebo because the symptoms were back.

My body, according to the info I received, lacks brown fat cells which metabolize, lacks an enzyme or two that also help prevent obesity (which runs in our family over at least 5 generations as do hypothyroid and kidney related problems). My physician and I have been looking for an effective treatment as exercise and diet have not worked for any female in our family line.

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