Looking for more research on LY354740

[arkhambreakout]

Looking for human studies on LY354740 and other mGluR agonists

This is a very interesting chemical and I'm just wondering, are there any more recent studies performed on humans? I would love to see what the potential is in therapeutic cases of severe / low-functioning autism (wishful thinking). There has already been speculation that it could help people with Fragile X but there's no studies. This has been around since the 80s, and it's almost making me want to get a PhD in chemistry so I can just do the studies myself.

Edit: Apparently there's a patent for it, after a little more digging -- https://patents.google.com/patent/US20150252049A1/en

 

[polymath]

I find that interesting too, having a mild form of autism spectrum disorder myself... The compounds of that type are probably not easy to produce synthetically, as they contain highly strained 3-carbon rings. There will probably never be a real "cure" for autism, though, because people with that kind of disorders have already built their lives around surviving with the disorder and it's difficult for an adult to learn completely new ways of behavior.

Compounds with an opposite effect, blocking the MGluR2/3 receptors, seem to intensify the effects of some drugs such as serotonergic hallucinogens, and may therefore also be interesting to some people.

 

[clubcard]

I see it is in the same class as the novel neuroleptics trialled in Russia. For over 2 decades I have argued that the 'dopamine hypothesis' did not account for at least 10% of people displaying schizophreniform disorders based on the fact that in sufferers, the levels of DOPAC in cerebrospinal fluid are elevated and/or NMDA levels are suppressed. Initially clozapine seemed like finally a non-refractive agent was on the market. That it indirectly increased NMDA levels was not appreciated at the time. Lilly trialled the class you referred to and in the demographic of those with suppressed NMDA levels, it was really effective. Sadly, a drug that is only going to work for 10 10% of patients isn't going to go onto the market and prevents anyone using the stuff in the future since it cannot be patented.

But in reference to your question - the cited patents/references tree out to multiple studies.

 

[adder]

There are very neat gold-catalyzed enyne cyclization reactions which can give such bicyclics, the compound actually looks like something that might have been prepared from a 1,5-enyne with proper substituents.

 

[Hodor]

I see it is in the same class as the novel neuroleptics trialled in Russia. For over 2 decades I have argued that the 'dopamine hypothesis' did not account for at least 10% of people displaying schizophreniform disorders based on the fact that in sufferers, the levels of DOPAC in cerebrospinal fluid are elevated and/or NMDA levels are suppressed. Initially clozapine seemed like finally a non-refractive agent was on the market. That it indirectly increased NMDA levels was not appreciated at the time. Lilly trialled the class you referred to and in the demographic of those with suppressed NMDA levels, it was really effective. Sadly, a drug that is only going to work for 10 10% of patients isn't going to go onto the market and prevents anyone using the stuff in the future since it cannot be patented.

But in reference to your question - the cited patents/references tree out to multiple studies.

Unfortunately, LY354740 ("Eglumegad") suffered from atrocious bioavailability.

They then came up with a pro-drug form, LY544344, which was transported into the cell via the Peptide Transporter 1 carrier protein, and initially showed significant promise... sadly, development of the drug was discontinued after it was found to give people convulsions during early pre-clinical trials.

 

[clubcard]

Unfortunately, LY354740 ("Eglumegad") suffered from atrocious bioavailability.

They then came up with a pro-drug form, LY544344, which was transported into the cell via the Peptide Transporter 1 carrier protein, and initially showed significant promise... sadly, development of the drug was discontinued after it was found to give people convulsions during early pre-clinical trials.

I did not know about the convulsions. Lilly obviously forgot to mention that when they stopped research - possibly so they could sell on the patent rights.

 

[polymath]

Another quite new drug target is the melanin-concentrating hormone receptor 1. Agonists increase appetite and indirectly decrease dopamine activity in the brain, but not in the nigrostriatal part, so they could be potential antipsychotics without parkinsonian side effects. They also seem to reduce repetitive behaviors in some animal model of autism. Antagonists of MCH-1 have an anxiolytic and antidepressant effect and they decrease appetite, so they could also have several applications.

 

[Hodor]

I did not know about the convulsions. Lilly obviously forgot to mention that when they stopped research - possibly so they could sell on the patent rights.

This is public info, though... it was posted in an academic journal in 2008.

Apparently Eli Lilly instead focused on developing the closely related drug "Pomaglumetad", or more specifically its prodrug form LY-2140023 (Pomaglumetad methionil), due to the former's shitty bioavailability. Sadly, it too was eventually abandoned, mostly because of a lack of superior efficacy compared to established antipsychotics, and possibly because of our old friend, "the serious adverse event of convulsion".

That said, in 2015, the rights to Pomaglumetad methionil were snagged by Denovo pharma.

 

[clubcard]

This is public info, though... it was posted in an academic journal in 2008.

Apparently Eli Lilly instead focused on developing the closely related drug "Pomaglumetad", or more specifically its prodrug form LY-2140023 (Pomaglumetad methionil), due to the former's shitty bioavailability. Sadly, it too was eventually abandoned, mostly because of a lack of superior efficacy compared to established antipsychotics, and possibly because of our old friend, "the serious adverse event of convulsion".

That said, in 2015, the rights to Pomaglumetad methionil were snagged by Denovo pharma.

I'm sure it did - but amazingly I can't read every single paper out there. It still makes a clear case that the dopamine hypotheses doesn't hold water since people without elevated levels of dopamine but with suppressed levels of NMDA present identical clinical symptoms.

At the moment neuroleptics share several traits that would see them refused a licence if it wasn't such an awfully disabling disease. Clozapine can cause agranulocytosis making it the last choice. Sadly, since so many related compounds were also patented, that means nobody is going to go back and look; they can't reliably get a patent. If you found a better homologue you MAY patent it based on the fact that it doesn't have such a dangerous side-effect BUT with the 20 year patent window providing an average of 7 years of licensed sales, Sandoz (in this case) can essentially cut themselves in since a year in court would potentially lose billions in sales.

 

[polymath]

There's also this compound with different kind of structure acting as MGlu2 positive allosteric modulator.

https://en.wikipedia.org/wiki/ADX-71149