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J147 - A new Alzheimers-reversing drug based on curcumin extract

alzheimers memory

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#1 Steve Zissou

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Posted 14 May 2013 - 01:05 PM


Just found this: http://www.utsandieg...turmeric-curry/

The drug candidate, called J147, reversed memory loss in Alzheimer’s model mice, according to a study published online Monday in the journal Alzheimer’s Research and Therapy. The study builds on earlier research finding that the drug preserves brain function when given to Alzheimer’s model mice. That study was published on December 2011 in the journal PLoS One.

The study compared J147’s memory-enhancing effects with Aricept, generically known as donepezil. It found that while both improved short-term memory, only J147 improved spatial memory. Moreover, combining the drugs worked better than either alone.

“It looks like an interesting compound that will have therapeutic utility, whether in AD or not; they have done a good job of characterizing the pharmacokinetics and safety,” Walker said by email, referring to how the body reacts to the drug.

After six years of preclinical studies, J147 is ready for human clinical trials, said Dave Schubert, head of Salk’s cellular neurobiology laboratory. The compound, derived from the curry spice component curcumin, has low toxicity and actually reverses damage in neurons associated with Alzheimer’s, said Schubert, the study’s senior author. The lead author is Marguerite Prior, a research associate in Schubert’s laboratory.


Sounds like an interesting substance, I would certainly like to give it a try.
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#2 BioFreak

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Posted 14 May 2013 - 01:46 PM

I wonder what sets it apart from plain curcumin. If it's the bio availability in the brain per oral route alone, then this has already been done (longvida curcumin). From personal experience with my grandma I can say that it does more likely halt and partially reverse the process... but not completely (1000mg a day split in 2 doses).

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#3 Steve Zissou

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Posted 14 May 2013 - 02:33 PM

Here is the contact information of one of the lead researchers here :http://www.salk.edu/faculty/schubert.html

#4 Googoltarian

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Posted 14 May 2013 - 02:46 PM

I wonder what sets it apart from plain curcumin


J147 is totally different molecule! Here you have overview which shows evolution of this drug from curcumin:
Attached File  untitled.jpg   31.74KB   85 downloads
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#5 theblob

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Posted 14 May 2013 - 04:43 PM

Mrs. Dr. Prior is kind of cute.

Posted Image

Cute researcher.

Edited by theblob, 14 May 2013 - 04:43 PM.

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#6 joostus

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Posted 14 May 2013 - 05:45 PM

First metabolism test looks great.

Metabolism of a potent neuroprotective hydrazide
Using a drug discovery scheme for Alzheimer's disease (AD) that is based upon multiple pathologies of old age, we identified a potent compound with efficacy in rodent memory and AD animal models. Since this compound, J147, is a phenyl hydrazide, there was concern that it can be metabolized to aromatic amines/hydrazines that are potentially carcinogenic. To explore this possibility, we examined the metabolites of J147 in human and mouse microsomes and mouse plasma. It is shown that J147 is not metabolized to aromatic amines or hydrazines, that the scaffold is exceptionally stable, and that the oxidative metabolites are also neuroprotective. It is concluded that the major metabolites of J147 may contribute to its biological activity in animals.


Chiruta, Chandramouli ; Zhao, Yanrong ; Tang, Fangling ; Wang, Tao ; Schubert, David
Bioorganic & medicinal chemistry, 2013, Vol.21(10), pp.2733-41 [Peer Reviewed Journal]
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#7 theblob

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Posted 14 May 2013 - 06:21 PM

Just discovered that J147 can be easely bought on cellagentech.com or millipore.com for 100 dollars / 5mg.
Kind of 9000 dollars for three months treatment. Not completely unaffordable. Someone has to try this.

Edited by theblob, 14 May 2013 - 06:30 PM.


#8 Steve Zissou

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Posted 15 May 2013 - 05:58 AM

9000 is a bit too steep, I wonder how much cheaper it would be if it was made in bulk.

"J147 was synthesized from 2,4-dimethylphenylhydrazine hydrochloride and 3-methoxybenzaldehyde in 2 steps with 71% overall yield. The precursor desmethyl-J147 was synthesized from 3-hydroxybenzaldehyde and 2,4-dimethylphenylhydrazine hydrochloride in 4 steps with 63% overall yield. [(11)C]J147 was prepared from desmethyl-J147 with [(11)C]CH(3)OTf through O-[(11)C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 35-50% radiochemical yield based on [(11)C]CO(2) and decay corrected to end of bombardment (EOB), with 370-740 GBq/μmol specific activity at EOB."

Can anyone with any chemistry knowledge chip in to as to why this compound is so expensive?
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#9 Googoltarian

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Posted 15 May 2013 - 07:48 AM

Can anyone with any chemistry knowledge chip in to as to why this compound is so expensive?


Mainly scarcity on the market plus it has to be made on small scale because demand for research is not in kilograms. Substrates are quite cheap, for example - 9000 dollars suggested by theblob could easily suffice to make ~1kg.
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#10 Psionic

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Posted 16 May 2013 - 08:33 AM

looks like it would be rather easier to make CNB-001

Posted Image

but if the J147 works in small doses then $9000 for a kilo can be very good price considering it even more effective than CNB-001 as mentioned in study below:


Curcumin is a curry spice with multiple biological activities that is also effective in transgenic AD mouse models [5], [6]. To improve the potency and pharmacokinetic properties of curcumin, we synthesized a series of hybrid molecules between curcumin and cyclohexyl-bisphenol A (CBA), a compound that has neurotrophic activity which curcumin lacks [7]. The best compound in our initial library was CNB-001, a molecule that has improved stability over curcumin and that is neuroprotective in multiple neurotoxicity assays in which curcumin is inactive [8]. We then generated a large number of derivatives of CNB-001 and selected the best compound on the basis of activity in our multiple toxicity assays. The result was a much more potent molecule called J147. It was then asked if J147 is effective in two paradigms of age-associated pathology, AD and memory. It is shown here that this broadly neuroprotective compound has the ability to enhance memory in normal animals as well as to prevent memory deficits in AD transgenic mice. The neurotrophic and memory-enhancing activities of J147 are associated with an increase in brain derived neurotrophic factor (BDNF) levels and the expression of BDNF responsive proteins, the enhancement of LTP, synaptic protein preservation, the reduction of markers for oxidative stress and inflammation, the reduction of amyloid plaques, and lower levels of soluble Aβ1–42 and Aβ1–40. These pleiotrophic effects of a single molecule suggest that J147 has potential for the treatment of AD.



Posted Image

http://www.plosone.o...al.pone.0027865

Edited by Psionic, 16 May 2013 - 08:41 AM.

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#11 BioFreak

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Posted 16 May 2013 - 01:56 PM

I wonder what sets it apart from plain curcumin


J147 is totally different molecule! Here you have overview which shows evolution of this drug from curcumin


Thanks for pointing that out.

#12 stponky

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Posted 17 May 2013 - 05:36 AM

Does any place have this that is not 'commercial supply' only?

#13 allstargajo

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Posted 27 May 2013 - 01:24 PM

What is the 'rule of thumb' when converting from mice dosage to human dosage?

From the paper

To explore the ability of chronic J147 treatment to stimulate various aspects of memory in young mice, they were fed J147 at 200 ppm (10–20 mg/kg/day) in their chow


So for someone of 70 kg would 700mg be what is desired?

#14 Psionic

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Posted 27 May 2013 - 01:37 PM

What is the 'rule of thumb' when converting from mice dosage to human dosage?

From the paper

To explore the ability of chronic J147 treatment to stimulate various aspects of memory in young mice, they were fed J147 at 200 ppm (10–20 mg/kg/day) in their chow


So for someone of 70 kg would 700mg be what is desired?


I dont think so, look for 'dose conversion table from lab animals to humans'. It should be approx. 50mg (divided by 12 fo a 70kg lab animal).

Now I wonder what a price quote can we get from some european trusted custom synth lab :)

#15 sk_scientific

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Posted 25 January 2014 - 04:00 AM

I wrote to these folks, to no avail. Has anyone followed up on the possibility of a synth?

#16 formergenius

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Posted 25 January 2014 - 04:54 AM

What a coincidence; I just saw someone trying to buy a kg of this on Alibaba today. Though, this was discovered in 2011, no?
Any updates on human trials?

#17 sk_scientific

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Posted 25 January 2014 - 06:18 AM

What a coincidence; I just saw someone trying to buy a kg of this on Alibaba today. Though, this was discovered in 2011, no?
Any updates on human trials?


None yet, sadly.

#18 HappyShoe

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Posted 11 April 2014 - 07:29 PM

Would it be possible to get this made via custom synth in a private lab? (Another group buy?)



#19 medicineman

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Posted 25 June 2014 - 04:45 PM

teamtlr.com is apparently going to carry this beauty.

Let me first say, I have absolutely no affiliation with these guys and I stumbled on them thanks to a friend here, but if they can get what they have on menu, I'd love to have a coffee with them.(I believe they can. I contacted them and they seem legit.) I guess the call for J147 was answered :)

Anyways, some extremely innovative stuff. Worthwhile if you are involved in preclinical trials on animal models.

Edited by medicineman, 25 June 2014 - 04:47 PM.

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#20 Nattzor

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Posted 25 June 2014 - 04:59 PM

teamtlr.com is apparently going to carry this beauty.

Let me first say, I have absolutely no affiliation with these guys and I stumbled on them thanks to a friend here, but if they can get what they have on menu, I'd love to have a coffee with them.(I believe they can. I contacted them and they seem legit.) I guess the call for J147 was answered :)

Anyways, some extremely innovative stuff. Worthwhile if you are involved in preclinical trials on animal models.

 

Was just about to post this, they'll also be carrying ISX-9 and JDTic (and tons more), really cool company. Everyone should just be careful testing this on all rats you have.


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#21 stponky

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Posted 26 June 2014 - 12:28 PM

teamtlr.com is apparently going to carry this beauty.

 

 

Wow, that is fantastic. I remember seeing the videos and then thinking "sounds wonderful, another chemical we will never see again". Congrats to teamtlr for doing this. We are getting some great compounds coming into the fold now. Exciting!



#22 OpaqueMind

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Posted 30 June 2014 - 10:48 AM

The effects of this compound look amazing. I just read the full paper, and the way they approached drug design was essentially to try to cover the key areas in which cognitive decline occurs with ageing eg inflammation, neuroptrophic factor decline, energy metabolism etc. But factors like these are not only related to the progressive decline of the brain, but also to immediate and short-term cognition. This is borne out by their observation that J147 also improved memory in the healthy control group. By designing a drug which targets all of these mechanisms simultaneously it looks like they've hit on one of the most comprehensive singular pharmacological approaches to maintaining the health of the ageing brain (and we're all ageing!), and possibly also one of the most comprehensive nootropics out there. Inflammation reduction and increased efficiency of energy metabolism in the brain should have immediately noticeable effects, with the upregulation of BDNF and increased neuro- and synapto-genesis taking slightly longer to maniest. Time will soon tell how it plays out. Many thanks to Medicineman and Nattzor for bringing teamtlr to our attention! What an incredible stock they have. Apparently their J147 is due in July, so we should have our first experience reports by August. Exciting times!



#23 HappyShoe

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Posted 09 July 2014 - 10:46 PM

Anyone know the dosages used on this? For humans in particular I mean.

Someone said 50mg? Is that right?


Edited by HappyShoe, 09 July 2014 - 10:47 PM.


#24 sk_scientific

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Posted 13 July 2014 - 03:58 AM

Anyone know the dosages used on this? For humans in particular I mean.

Someone said 50mg? Is that right?

 

I'll figure out the H.E.D. tomorrow if I can find publication material.  If memory serves me correctly I believe it was in the 30 mg range for an individual that weighed around 190 pounds but don't quote me on it until I get back to you.


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#25 sk_scientific

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Posted 13 July 2014 - 03:45 PM

It looks like transgenic mice were fed between 1 and 10 mg/kg daily, depending on the study.  So we'll go with a conservative estimate on H.E.D., accounting for unknowns (as one should), say 3 mg/kg

 

HED (mg/kg) = Animal Dose (mg/kg) x [Animal Km / Human Km]

Human Km = 37

Mouse Km = 3

Rat Km = 6
=============

3mg x [3/37] = 0.243243243 mg/kg

 

and
 

190 lb male = 86.1826 kg

 

so

 

86.1826 kg x 0.243243243 mg

 

Equals

20.963335135mg, QD for an 190 lb male

 


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#26 resveratrol_guy

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Posted 02 October 2014 - 06:23 PM

 Apparently their J147 is due in July, so we should have our first experience reports by August. Exciting times!

 

[Mods: Here's the other J147 thread. Maybe they should be merged.]

 

I think this compound is receiving way too little attention here on Longecity, considering the memory benefits that it offers to healthy as well as Alzheimers mice.

 

It's now "highly limited -- due in September", i.e. last month,  from TrueLIFE Research (teamtlr) here.

 

Also available here from Tocris.

 

Both of the above are quite more than $9000/kg as suggested above, but might be more appropriate quantity for a small trial.

 

I would think Longecity's dihexa enthusiasts would be quite interested, so perhaps we can reach a useful economy of scale to get this underway, perhaps by leveraging their existing trusted supply chain.

 

BTW there's apparently an ongoing ALS trial described here, but I don't see any current updates since it was fully funded.

 


Edited by resveratrol_guy, 02 October 2014 - 06:37 PM.


#27 sk_scientific

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Posted 06 October 2014 - 04:31 AM

Bump.

 

Waiting on teamtlr to write me about the synth

 



#28 Megatrone

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Posted 06 October 2014 - 11:29 AM

Bump.

 

Waiting on teamtlr to write me about the synth

 

Let us know. This compound is so exciting!


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#29 resveratrol_guy

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Posted 12 November 2014 - 03:12 PM

Bump.

 

Waiting on teamtlr to write me about the synth

 

It's now "Highly Limited - Due in November". Since you have existing correspondence with them, can you please follow up in case they forgot? Sorry to be annoying, but my friend with early dementia really wants this, and would make an instructive test subject for the benefit of the community.



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#30 OpaqueMind

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Posted 12 November 2014 - 03:21 PM

I inquired about the progress of the synthesis a couple weeks ago, and received this message in return - 

 

"The synthesis as given in the literature was reasonably facile, however, it as well was not at all viable (oddly).

As such it has proven to be a formidable situation and has been worked on extensively.  Word on what is what is expected this week, but I would advise one not to hold one's breath, ;) "

 

Basically, they're working on it, but the due date is unknown and could be a while. Props to them for not giving up on it and trying to come up with a whole new synthesis route.


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