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October 2, 2008
Taranabant Is No More
Posted by Derek
Merck has taken a step that many people have been expecting, and announced that they are no longer developing taranabant, their cannabinoid antagonist (or is it an inverse agonist?)
I'd expressed grave doubts about the drug earlier this year, which turned out to be well-founded. That latter post included the line "I don't see how they can get this compound through the FDA", and now Merck seems to have come to the same conclusion. Further clinical data seem to have shown far too many psychiatric side effects (anxiety, depression, and so on), which increased along with the dose of the drug.
The cannabinoid antagonist field has already experienced a crisis of confidence after Sanofi-Aventis's rimonabant failed to gain approval in the US. This latest news should ensure that no company tries to develop one of these drugs until we've learned a great deal more about their pharmacology. Given how little we know about the mechanisms of these mental processes, though, that could take a long, long time. We can pull the curtain over this area, I think.
Comments (15)
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1. Tommy Chong on October 2, 2008 12:14 PM writes...
I am not a pharmacologist, but who thought that antagonizing a receptor - which when filled by window-box grown agonist makes the patient happy and mellow - would not make one unhappy and unmellow?
Permalink to Comment2. Timothy Leary on October 2, 2008 1:27 PM writes...
"I am not a pharmacologist, but who thought that antagonizing a receptor - which when filled by window-box grown agonist makes the patient happy and mellow - would not make one unhappy and unmellow?"
And I would further posit that blockade of the 5-HT2A receptor will cause you to act like Dick Cheney.
Permalink to Comment3. satan on October 2, 2008 3:44 PM writes...
The worst ideas always begin with 'experts' saying-
" We are different"
" This time is different"
" This cannot happen to us"
" This is a new paradigm"
Ironically, 'experts' are always caught flat-footed when the paradigm changes or things are different.
Permalink to Comment4. ex-UK Pharma on October 3, 2008 2:46 AM writes...
Ah, the antagonist / inverse agonist cannabionoid game. My former employers had a CB1 project, I was peripherally involved doing some in-vitro functional screening.
It seemed as though every project meeting was a reverse on the previous one. "We want an antagonist". Next meeting "Actually, maybe an inverse agonist would be better, let's chase that". Lather, rinse, repeat.
Permalink to Comment5. Petros on October 3, 2008 8:09 AM writes...
Don't forget that one of the efefcts of smoking weed is "the munchies"
So CB1 receptor activation appears to stimulate appetite.
Permalink to Comment6. Petros on October 3, 2008 8:18 AM writes...
Quite a few in development
otenabant Pfizer Phase III antagonist
drinabant sanofi-aventis phase II antagonist
surinabant sanofi-aventis phase II antagonist
ibipinabant Solvay/BMS phase II antagonist
AZD-2207 AstraZeneca phase II antagonist
Org-50189 Schering Plough phase I antagonist
Permalink to CommentAZD-1175 AstraZeneca phase I antagonist
rosonabant Esteve Phase I inverse agonist
7. Selene on October 3, 2008 2:19 PM writes...
So Pfizer's candidate now has a name? They list it in their Sept 30 pipeline update as a number and AFAIK always have done so.
Also considering the lack of success of rimonabant and now taranabant, how much time and effort is sanofi likely to put into those phase II candidates?
Permalink to Comment8. Maks on October 4, 2008 1:38 PM writes...
Does anyone know why almost all CB1 antagonists are actually inverse antagonists? Is is just "bad" chemistry or an intrinsic property? The only one I'm familiar with which is a silent agonist is cannabivarin which is in clinical trials by GW Pharmaceuticals.
Permalink to Comment9. leigh on October 4, 2008 10:55 PM writes...
the field doesn't know how to separate the psych effects from the energy balance effects. the cb1 receptor is so freaking ubiquitous that an antagonist/inverse agonist affects all kinds of things. i find myself asking whether they can be separated at all with our current level of skill and knowledge.
Maks, there are several compounds that appear to be neutral antagonists, but i haven't seen much research on them. the ones we hear about, and the ones generally used in study of cb1 receptors, happen to have inverse agonist properties. rimonabant is a long-lived staple in cb pharmacology.
Permalink to Comment10. rosie on October 5, 2008 1:10 PM writes...
I am sorry, but I believe in this drug! I have been taking it slightly less than 2 years and have terrific results with no bad side effects! I will be very sorry to go to the clinic tomorrow to turn in un-used pills and end the study. I just hope another one (as good) comes along!
Permalink to Comment11. Dr. Helen Bin on October 18, 2008 8:19 AM writes...
"I am sorry, but I believe in this drug! I have been taking it slightly less than 2 years and have terrific results with no bad side effects! I will be very sorry to go to the clinic tomorrow to turn in un-used pills and end the study. I just hope another one (as good) comes along..."
I completely agree, but would like to state the opinion and special expert addition ...
Permalink to Comment12. Petros on October 27, 2008 8:31 AM writes...
And now the EU has pulled Accomplia on safety grounds.
Permalink to Comment13. Petros on November 6, 2008 6:53 AM writes...
And now Pfizer has pulled otenabant (in phase III) saying it showed no adverse effects but citing the unfavourable regulatory climate!
Permalink to Comment14. Kat on February 2, 2009 7:27 PM writes...
Hi - I took Acomplia from September 2006 through the pull last November. All I can say is that after 40 years trying to battle my weight to no avail, Acomplia helped me drop 50lb and did not alter my mood adversely. I do realize that the incidence of depression is high 8% - but I believe with appropriate monitoring, this drug is a Godsend for those that tolerate it.
Permalink to Comment15. Kat on February 2, 2009 7:28 PM writes...
Hi - I took Acomplia from September 2006 through the pull last November. All I can say is that after 40 years trying to battle my weight to no avail, Acomplia helped me drop 50lb and did not alter my mood adversely. I do realize that the incidence of depression is high 8% - but I believe with appropriate monitoring, this drug is a Godsend for those that tolerate it.
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