RL648_81: Synthesis and Evaluation of Potent KCNQ2/3-specific Channel Activators

[attheedgeofscience]

Since about a year and a half, the involvement of certain Kv7-channels in relation to the induction of tinnitus, has been closely followed by a large number of members of TinnitusTalk. Retigabine is known to target this set of Kv-channels (with the addition of Kv7.4/5). The potential for Retigabine to prevent the development of tinnitus (following noise exposure) was indicated in a 2013-article by the well known tinnitus researcher, Prof. Tzounopoulos:

http://www.dailymail.co.uk/health/a...TINNITUS-reduces-hyperactivity-cells-ear.html

Towards the end of 2014, and as part of [USERGROUP=11]@Team Trobalt[/USERGROUP], I got in touch with Prof. Tzounopoulos to learn more about the mechanism-of-action of Retigabine (in relation to tinnitus). From that correspondence, I came to know about a novel Kv-channel opener with increased selectivity and greater potency than Retigabine - the reply can be seen here:

https://www.tinnitustalk.com/thread...-—-petition-to-the-ata.6896/page-4#post-80103

The new compound mentioned in that correspondence turned out to be SF0034. As part of the on-going efforts of Team Trobalt, I learnt during the spring of 2015 that, yet another development was underway. I therefore also knew - as with what turned out to be SF0034 - that there was yet another development to unfold at some point in the future. That development came to the surface, when, Monday this week, I learnt that the manuscript pertaining to yet another and yet more potent Kv-channel opener had been released. The name of the lead compound is RL648_81.

Before any of the news articles were published, I managed to briefly get feedback from one of the co-authors of the paper - in particular to learn if tinnitus would be in scope of a future clinical trial. The feedback was: "We are certainly planning for a tinnitus development, but we are still pursuing preclinical studies..."

Given the disappointing news from the QUIET-1 study of Autifony Thereapeutics in 2015, I believe that there is yet again room to be at least cautiously optimistic for a future treatment of tinnitus.

Read more about the development via the link below.

 

[attheedgeofscience]

A New Kv-Channel Modulator: RL648_81

From one of my sources, it has come to my attention that Prof. Tzounopoulos has just this past week published another paper on a compound called "RL648_81" - a more potent and selective compound than SF0034 (and SF0034 was already more potent/selective than Retigabine). I have only just now received the information and I have therefore not had time to read the 45-page paper (so the above is just the basics).

Attached is the full text manuscript.

 

[Zechariah]

A New Kv-Channel Modulator: RL648_81

From one of my sources, it has come to my attention that Prof. Tzounopoulos has just this past week published another paper on a compound called "RL648_81" - a more potent and selective compound than SF0034 (and SF0034 was already more potent/selective than Retigabine). I have only just now received the information and I have therefore not had time to read the 45-page paper (so the above is just the basics).

Attached is the full text manuscript.

If I recall right, someone (sort of official source/weblink) tried to discredit SF0034 by saying something like: "Fluorination is well known procedure and it was most likely tried to Retigabine aswell - there won't be more potent Kv7 modulator".

Well it's kind of funny that these more and more potent drugs keep showing up as a result of this "well known process" which was "already tried" on Retibagine.

EDIT: This statement may have been part of the "attack" against SciFluor some time ago.

 

[valeri]

How on earth would he know it's better or more potent when none have been tested?

 

[Frédéric]

Hi, I have just found this link, it's an update :
http://www.eurekalert.org/pub_releases/2016-03/uops-ptr032916.php

 

[lapidus]

How on earth would he know it's better or more potent when none have been tested?

http://www.eurekalert.org/pub_releases/2016-03/uops-ptr032916.php
In this article from yesterday about RL-81 they write the following:

"When the researchers compared the three drugs head-to-head in lab tests, they found RL-81 was 15 times more potent than retigabine and three times more potent than SF0034. Because of its specificity, RL-81 also should have fewer side effects."

So I guess "lab tests" answer your question

 

[Cheza]

Hi, I have just found this link, it's an update :

It sounds promising, doesn't it?

Excerpt:
Researchers at the University of Pittsburgh School of Medicine and Arts & Sciences have designed a more effective version of an FDA-approved epilepsy drug with the potential for fewer side effects, according to a study published on March 22 in Molecular Pharmacology. The experimental agent also could prove to be a treatment for tinnitus and other disorders caused by volatile neural signaling.

Excerpt:
When the researchers compared the three drugs head-to-head in lab tests, they found RL-81 was 15 times more potent than retigabine and three times more potent than SF0034. Because of its specificity, RL-81 also should have fewer side effects. The experimental compound could also help people with tinnitus by preventing hyper-excitation of nerve cells in auditory pathways, Dr. Tzounopoulos noted.

Well, this is good news. Do you suppose docs will prescribe it off-label for tinnitus, considering Dr. Tzounopoulos' reference to tinnitus?

Are we looking at two to three years for FDA approval following clinical trials? Is it possible the drug will be approved in Europe long before that?

 

[Carlos1]

Don't want to get my hopes up but geez it does sound promising
Just reading this article gives me strength to keep battling and believe that there will be a cure in my life time. I'll be so F***ing pumped I won't know what to do.

 

[monacco]

@Cheza When I was on trobalt my T decreased from 7 to 3 so if realy RL-81 is 15 times more portent than trobalt my t will decrease from 7 to - 45

 

[valeri]

http://www.eurekalert.org/pub_releases/2016-03/uops-ptr032916.php
In this article from yesterday about RL-81 they write the following:

"When the researchers compared the three drugs head-to-head in lab tests, they found RL-81 was 15 times more potent than retigabine and three times more potent than SF0034. Because of its specificity, RL-81 also should have fewer side effects."

So I guess "lab tests" answer your question

Thank you!
That's a good news but I guess until they start proper human trials we are still left with little hope

 

[Poyraz]

Oh God! That sounds so promising. I hope this drugs will also be for idiopathic Tinnitus.

 

[lapidus]

Are we looking at two to three years for FDA approval following clinical trials? Is it possible the drug will be approved in Europe long before that?

If there's one thing I've learned from coming to this forum, it is that research and drug testing takes a LONG time. So personally, I wouldn't count on it. But since this is an "upgraded version" of an already existing drug, maybe the process could go faster with this? Anyone with research insight who knows? @Gill Hayes ? @Silvio Sabo ?

 

[Ecip]

https://www.sciencedaily.com/releases/2016/03/160330102848.htm

"At this point, the new compound is ready to be studied further in animal models of epilepsy and tinnitus and for other preclinical assessments," Dr. Wipf said. "RL-81 appears to have great potential for the treatment of these challenging neurological conditions."

 

[Reinier]

decrease from 7 to - 45

What is negative tinnitus?
Tinnitus is negative (-;

 

[Kane Moffat]

Realistically speaking, when is the earliest we would expect to get our hands on either sf00034 or RL-81.

 

[Silvio Sabo]

Realistically speaking, when is the earliest we would expect to get our hands on either sf00034 or RL-81.

Don't expect anything before 2020. The drugs still have to be tested. Perhaps a more suitable date is sometime 2025-ish.

I think a more viable shorter term solution is either gene therapy or stem cell therapy. When it comes to drugs it always takes a looooooong time. Treatments that don't require approval of new drugs are usually faster especially since gene therapies as well as stem cell therapies have been done before for other things.

 

[Mithrandir]

That's always good for next generation... Stem cell sounds good like ATEOS/fernando gil/ or other persons on the web showed us...but the problem is always to target cochlea. Can we try very expensive stem cell treatment and hope that function whereas we have no idea about the exact efficacy ? That's a big investment.

 

[Mithrandir]

That's a great news for all T sufferers & give hope. People can try RTG now even if that's not enough potent than the future compound. Personally I made a RTG trial with no good results...no real improvement on my T/H.

I wish you all a good RTG trial & hope

 

[AlecP]

Very interesting and exciting stuff. I know it's best to exercise caution with news like this but it shows that work is being carried out and progress is slowly being made. Nevertheless, hopefully something awesome comes of this!

 

[Silvio Sabo]

That's always good for next generation... Stem cell sounds good like ATEOS/fernando gil/ or other persons on the web showed us...but the problem is always to target cochlea. Can we try very expensive stem cell treatment and hope that function whereas we have no idea about the exact efficacy ? That's a big investment.

I'm pretty sure there are ways to target specific organs using stem cells.

 

[Reinier]

I think a more viable shorter term solution is either gene therapy or stem cell therapy.

Do you say this because (as an example) the doctor in America using stem cells was able to "by pass" lengthy test and approval mechanism (clinical trials)?
I wonder if we can expect more stories like this?
Perhaps the law makers would like to stop this.
Does this also apply for gene therapy?
The moment you start molecular cell biology you will need drug approval?
I know: many questions (-;

 

[Silvio Sabo]

Do you say this because (as an example) the doctor in America using stem cells was able to "by pass" lengthy test and approval mechanism (clinical trials)?
I wonder if we can expect more stories like this?
Perhaps the law makers would like to stop this.
Does this also apply for gene therapy?
The moment you start molecular cell biology you will need drug approval?
I know: many questions (-;

The thing is that when it comes to treatments you will always be able to go to countries that don't make it illegal to get one. Drugs are a bit tricky since no drug company is going to invest in a drug they won't be able to sell everywhere. Especially if they can't sell it on big markets like the US or Europe.

Stem cell therapies have already been used as well as gene therapies. The first time gene therapy was used was in 1990.

There are already places where they do stem cell treatments. The only thing they have to do is find a solution for how to treat tinnitus with it and they would probably be ready to go tomorrow, not in 10 years. This of course depends on how soon they find a solution with such a treatment.

This is why I think that a solution with such a treatment will be able to be available sooner then drugs.

Yes you might not be able to get it in your home town or even home country but if you really want it and need it you'd still be able to travel somewhere and get it.

Also stem cell therapies or gene therapies would probably fix the problem permanently. If you repair the damage there is no need to take drugs continually on a daily basis.

 

[Reinier]

@Silvio Sabo I like your positive post.
Yet there are still drug companies investing in developing a drug for hearing loss. So I assume they decided that stem cell or gene therapy will not be the better solution for hearing loss.
I understand it is not black or white/this or that. It is so complicated!

And more important: perhaps stem cell therapies and gene therapy for the inner ear have not yet been investigated to such an extend that we can know the full potential. It is (for hearing issues) at its infancy.

 

[Silvio Sabo]

@Silvio Sabo I like your positive post.
Yet there are still drug companies investing in developing a drug for hearing loss. So I assume they decided that stem cell or gene therapy will not be the better solution for hearing loss.
I understand it is not black or white/this or that. It is so complicated!

And more important: perhaps because stem cell therapies and gene therapy for the inner ear has not yet been investigated to such an extend that we can know the full potential. It is (for hearing issues) at its infancy.

Drug companies investing in drugs and not investing in treatments that could actually cure something and that would not require you to take their drug on a daily basis for the rest of your life?! I'm shocked!

The fact that someone is investing in something does not mean it's the best way to go or the only way to go. Drug companies develop drugs - it's what they do - just the same as bakeries bake bread and don't do tax advising.

It is a good thing that there is a broad spectrum of approaches. The more ways tinnitus is targeted the bigger the chance that someone will find a solution. So I'm not saying it's a bad thing that drugs are being developed.

However I still believe that therapies that fix the damage are going to be the way to go in the end over drugs even if we find drugs that work. It will be cheaper and all in all a better solution for the individual than having to take drugs forever and ever. Treatments that repair the body are a thing of the future. Big pharma approach has it's limits and will surly be abandoned at some point. Maybe not in our lifetime but at some point we will no longer develop drugs to treat diseases but fix the problem instead of putting a patch over it.

 

[Reinier]

The fact that someone is investing in something does not mean it's the best way to go or the only way to go.

That would not be sound business practise. If you invest a huge amount of money in a drug and there is a good change that stem cell or gene therapy will do the same or even better, nobody will buy/use your drug. But I could understand it may not be the only way to go. This means that a drug may still be needed and than I can understand the investment in a drug.

However I still believe that therapies that fix the damage are going to be the way to go in the end over drugs even if we find drugs that work.

My point of view to. Regenerating and at the same time getting rid of tinnitus, hyperacusis etc...
Bliss.

 

[Silvio Sabo]

That would not be sound business practise. If you invest a huge amount of money in a drug and there is a good change that stem cell or gene therapy will do the same or even better, nobody will buy/use your drug. But I could understand it may not be the only way to go. This means that a drug may still be needed and than I can understand the investment in a drug.

As I said this is a matter of opinion as well as company practice and history. If everyone that invested big money did it wisely all the time the world would look very different. There are people investing in stem cells and gene therapies as well.

There will always be people who think differently and put their money in what they believe in or what they've always put their money in previously. And there will always be people putting their money on things that compete with something that someone else has put big bucks into. This is what promotes progress. There where people making big investments in developing typewriters once. But that's not the way to go today now is it?

It isn't a bad thing to invest in drugs today. There is a big chance that you will make money on your investment. The people who invest money in drugs are probably aware of the fact that the future might not be in their favor but investing in a drug today is still profitable. And so they do it. In 10 years they might change their mind. Who knows. And of course a drug company will put their money on drugs. It's what they do! It's what they've always done. It's the company strategy.

But the list of companies that have gone belly up or very close to it because they didn't adapt to changes over time is a long one. Kodak - who were a huge corporation once, a world leader in photography and camera technology - for example thought that digital photo was going to be just a fly. You have CEOs for fortune 500 companies saying internet was just going to be a short lived "thing". Just because you have big bucks don't mean you're right.

 

[Bertman]

This is some "cautiously" great news because in my opinion, it suggests that these Kv channels have at least a some chance at reducing T levels for many of us (and hopefully preventing noise spikes). I say this because I don't think great minds like Prof Tzounopoulos would create yet another drug candidate (after sf0034) if they weren't certain of it's effectiveness (although it's main function is for epilepsy, so who knows for us).

http://www.ca-biomed.org/pdf/media-kit/fact-sheets/CBRADrugDevelop.pdf
It says the average time is about 12 years for a drug to go from the lab to the patient. So hopefully since sf and this new drug build upon an existing drug, it may be sped up a bit. Also, as Prof T mentions, many (up to a third) people don't react to current epileptic drugs, so there is definitely still an unmet need, which may also speed it up (wishful thinking). Keep in mind only a very small percentage of drugs make it to market though.

Lastly, they keep mentioning noise induced T during their research. I wonder if there is a certain characteristic of this cause that would make it react differently to treatments than other causes. My line of thinking is that it is just easier to research mice using this process as it seems to be the easiest way to produce tinnitus with some level of certainty in animals.

best wishes everyone/

 

[Bertman]

Also, who would be the pharma company that would be bringing this to trials, or is there one yet? Cause that could be a long delay if there is a lack of funding.

 

[Mithrandir]

Well we'll buy RTG during long time again !

 

[valeri]

As I said this is a matter of opinion as well as company practice and history. If everyone that invested big money did it wisely all the time the world would look very different. There are people investing in stem cells and gene therapies as well.

There will always be people who think differently and put their money in what they believe in or what they've always put their money in previously. And there will always be people putting their money on things that compete with something that someone else has put big bucks into. This is what promotes progress. There where people making big investments in developing typewriters once. But that's not the way to go today now is it?

It isn't a bad thing to invest in drugs today. There is a big chance that you will make money on your investment. The people who invest money in drugs are probably aware of the fact that the future might not be in their favor but investing in a drug today is still profitable. And so they do it. In 10 years they might change their mind. Who knows. And of course a drug company will put their money on drugs. It's what they do! It's what they've always done. It's the company strategy.

But the list of companies that have gone belly up or very close to it because they didn't adapt to changes over time is a long one. Kodak - who were a huge corporation once, a world leader in photography and camera technology - for example thought that digital photo was going to be just a fly. You have CEOs for fortune 500 companies saying internet was just going to be a short lived "thing". Just because you have big bucks don't mean you're right.

I hope nobody bought Autifonys shares as there was a lot of talk about it