Science/Techno Babble Random, Random

[ptmcmahon]

Why does this feel like an April Fools joke?

[ponchi101]

Meta? With an infinity symbol?
How on earth does this improve their brand? It will still be the same thing, right?

[Suliso]

Same way as Google was improved by rebranding itself as Alphabet?

[ti-amie]

Just think someone got paid six figures to come up with that name.

[Suliso]

The latest two drugs showing very high promise for treating covid



Paxlovid by Pfizer



Molnupiravir by Merck


Molnupiravir looks to me like a typical nucleoside based antiretroviral (HIV drugs have similar structures). Pfizer compound is more unusual and also far more complex. Would need to read up where that one comes from.

[ponchi101]

The latest two drugs showing very high promise for treating covid



Paxlovid by Pfizer



Molnupiravir by Merck


Molnupiravir looks to me like a typical nucleoside based antiretroviral (HIV drugs have similar structures). Pfizer compound is more unusual and also far more complex. Would need to read up where that one comes from.

I felt EXACTLY the same way (What you do amazes me with frequency).
Thanks for that. If you don't mind: why the triple Fluorine group in Paxlovid? Wouldn't that be totally non-binding to anything? With Fluor's last "orbit" being full, it would not even be electrically charged.

[JazzNU]

The latest two drugs showing very high promise for treating covid

Molnupiravir looks to me like a typical nucleoside based antiretroviral (HIV drugs have similar structures). Pfizer compound is more unusual and also far more complex. Would need to read up where that one comes from.

Maybe the reason for the difference in success rates in the two drugs? One more complex and potentially more targeted specifically to covid?

[Suliso]

Molnupiravir looks to me like a typical nucleoside based antiretroviral (HIV drugs have similar structures). Pfizer compound is more unusual and also far more complex. Would need to read up where that one comes from.

I felt EXACTLY the same way (What you do amazes me with frequency).
Thanks for that. If you don't mind: why the triple Fluorine group in Paxlovid? Wouldn't that be totally non-binding to anything? With Fluor's last "orbit" being full, it would not even be electrically charged.

What follows is a speculation only. I don't know anything about the binding pocket of this particular substance.

It is true that fluorine rarely engages in active binding (weak hydrogen bonding is known), however trifluoromethyl group might be just occupying a hydrophobic pocket "fixing" the target in the active site. The logical follow up question would be why not just methyl? To that there is a more straightforward answer. Methyl would likely be metabolically labile both oxidatively and hydrolytically (enzymatic cleavage of acetyl group) plus CF3 is more lipophilic (= better soluble in fats)

In general fluorine substituents are common in both pharmaceutical and and agrochemical products for the following reasons:

- hydrophobic "binding" due to increased lipophilicity
- guarding against metabolic lability. Enzymes tend to be inert against C-F bond as it's virtually unknown in nature
- changing 3D geometry in a specific manner due to large dipole moment

In my limited experience (I'm actually a process not medicinal chemist) the second reason is the most prominent.

[Suliso]

The latest two drugs showing very high promise for treating covid

Molnupiravir looks to me like a typical nucleoside based antiretroviral (HIV drugs have similar structures). Pfizer compound is more unusual and also far more complex. Would need to read up where that one comes from.

Maybe the reason for the difference in success rates in the two drugs? One more complex and potentially more targeted specifically to covid?

That seems to be the case. They say Paxlovid is the first drug specifically targeting covid, Merck compound is more of a general antiretroviral (typical structure, even I recognized). Although it must have been in development for something else before, time passed since covid appeared is not long enough to have finished a dedicated development program all the way to Phase 3 clinical trials. The below text is from in the Pipeline blog hosted by Science magazine:

-------


We have more good news on the small-molecule anti-Covid front. We’ve already seen what look like strong results with molnupiravir, the Merck/Ridgeback/Emory transcriptase inhibitor. Everyone has been waiting on the results of Pfizer’s protease inhibitor (PF-07321332, now named Paxlovid), which would represent is the first small molecule trial results from a compound that was explicitly aimed at a SAR-CoV-2 protein (here it is in complex with the protease target itself). Remember, molnupiravir is more of a general viral RNA transcriptase inhibitor, and was around before we knew about the current coronavirus.

We’re getting the protease inhibitor news well before it was expected, because the results were so strong. Told you it was good news! Pfizer’s press release this morning says that when its EPIC-HR trial ran its scheduled interim analysis, it showed an 89% reduction in hospitalization or death when the drug was given to high-risk patients within 3 days of symptom onset, and 85% reduction when given within 5 days. There have, in fact, been no deaths at all in the treatment groups after 28-day follow-up. The trial has now been stopped due to efficacy (they had only made it up to 70% enrollment by that point), and the company is moving up its EUA application as quickly as possible. Note that the treatment regime includes a smaller dose of ritonavir, which is in there not for its antiviral activity (it’s useless as a direct antiviral against the coronavirus), but for its CYP-inhibiting properties, slowing down the metabolic clearance of the actual drug.

Step back for a moment and consider that this is really as fast as you could possibly expect a new, targeted small-molecule drug to ever be developed. Pfizer has a history in the antiviral protease world, so they had the expertise (and the screening collection!) to get a strong start. But here we are, less than two years after the emergence of this pathogen, with a bespoke drug against it. That's the speed record, and I think that it will be very, very hard to break - and I hope that we never have to try! It's a remarkable accomplishment.

I look forward to more details than we have now, but these are obviously strong numbers. Pfizer obviously split out the treatment groups by timing of the dose, and earlier is clearly better. But if you take it crudely as “Everyone dosed with the drug out to five days from symptoms”, then there were 9 people in the treatment group hospitalized out of 996 total and zero deaths, compared to 68 hospitalized out of 997 patients and ten deaths. So if indeed we can eliminate almost 9 out of 10 hospitalizations and virtually all deaths in high-risk patients with an oral drug that’s given only once symptoms appear, the course of the pandemic can clearly be altered. And then remember the strong molnupiravir results, and remember that that drug still has a trial to report where it’s used as a prophylactic treatment in high-risk patients as well: all this has to be the best treatment news we’ve had since the beginning of the pandemic. Previous successes (such as the use of dexamethasone) have helped save people once they’re in the hospital, but we’re now talking about keeping them from ever being hospitalized in the first place. And we can add in the fluvoxamine results that I blogged about yesterday, too, on what's probably the anti-inflammation front.

Let’s think about some of the implications: first, an utterly obvious question is whether molnupiravir and Paxlovid can be combined into a cocktail regimen, as we have seen for other viral diseases like HIV and Hepatitis C. Those are by far the most successful small-molecule antiviral treatments ever discovered, and there seems to be no reason why this situation wouldn’t be similar. Why would you want to do this? Well, increased efficacy, clearly, but also to decrease the chances of a resistant coronavirus emerging. We already have evidence that it’s difficult to develop resistance to molnupiravir (because of its mechanism, which differs from other commonly used transcriptase inhibitors). But molnupiravir hasn’t been given to millions of patients yet. I have not yet seen similar in vitro resistance experimental results with Pfizer’s protease inhibitor, but you’d have to expect that resistance is easier to develop. Giving the two drugs at the same time would then be even more in Pfizer’s interest, as it would help to protect the efficacy of their compound. Meanwhile, avoiding a drug-resistant strain of the coronavirus would certainly be in the interest of the rest of the world. Now, there's no reason to assume that such a protease-resistant form of the virus would be able to compete with wild-type Delta in the general population, but we would very much not want to find out the hard way.

Second, we have to think about distribution and price. Merck has already announced that it will license out its molnupiravir IP to the UN's Medicines Patent Pool, which will have the effect of making the drug much cheaper in developing countries and more widely available as other generic companies produce it. Pfizer is going to have to address this issue as well. The chemical synthesis of these compounds is technologically much more straightforward than that needed for the mRNA vaccines, and there should be no reason that the process can’t be run by any country with competent generic drug manufacturers. Pfizer has said that it is “committed to working toward equitable access” and that it is “exploring potential contract manufacturing options”. They had better.

Third, picture what effect this will have on the pandemic and on its treatment options. The hope is that this sort of small-molecule treatment will be able to keep the vast majority of coronavirus patients out of the hospital, which will obviously be a huge help for overburdened healthcare systems around the world. The availability of an oral pill regimen that keeps the disease from getting bad (and from killing you!) will come as a great relief psychologically. The vaccines have been tremendous - it's even better not to get the coronavirus in the first place, and I don't even want to think about what the Delta wave would have looked like without them. But there are breakthrough infections that no one is happy about, and even more than that there are just too many people unvaccinated - which is especially galling in countries that have plenty of free vaccine waiting for everyone, but that's another subject.

But one thing that this oral treatment option will probably do is push the monoclonal antibodies even further off to the side. They're given i.v. in a hospital setting, and the plan is to keep people from ending up in the hospital in the first place. This should also push remdesivir demand down to zero. It was never a very effective drug, even under the most optimistic view of the data, and now there would seem to reason for it to be used at all. And perhaps we can all stop hearing about ivermectin and hydroxycholoquine and all the other things that have by now been shown over and over not to be useful, but that may be too much to hope for. At any rate, as treatment options expand, that stuff is going to look even more perverse than it does already, which is saying something.

All in all, it appears that we are turning yet another corner in the story of our fight against this virus - and perhaps there aren't many more of them coming? We have vaccines and now we have effective drugs to be given early in the course of the disease. How many infectious diseases have more than that? Think about it - why shouldn't we now be able to beat this pandemic back into the ground? Let's get on it.

https://www.science.org/content/blog-po ... -good-news

[Suliso]

A one version of top 10 mathematicians of all time found on the Internet.

1. Leonhard Euler (1707-1783)
2. Carl Friedrich Gaus (1777-1855)
3. Bernhard Riemann (1826-1866)
4. Archimedes (ca 287-ca 212 BC)
5. Srinivasa Ramanujan (1887-1920)
6. Euclid of Alexandria (4th century BC)
7. Rene Descartes (1596-1650)
8. Isaac Newton (1642-1726)
9. Gottfried Wilhelm von Leibnitz (1646-1716)
10. Pierre de Fermat (1607-1665)

[ponchi101]

Uhm, Euler over Gauss. That is a tough one. I know that Euler did a lot of things with e and his method for approximation is one of the best tools for integration, but Gauss was all over math and contributed to almost all fields. Not to mention, he formalized statistics and gave it the most solid footing possible. I would revert those two.
Riemann at 3rd I am Ok with.
Ramanujan at 5 over Newton and Leibnitz is also a bit problematic. Sure, he was a genius, self taught, and basically developed all of math again before being found, but most of his work was in number theory. The other two developed calculus, and of course until very recently, calculus was clearly more important. Number Theory became of relevance with encrypting technology.
Fun list.

[Suliso]

Newton would probably be found on the list of greatest physicists as well. Definitely one could argue about the order or some omissions, it's just for fun anyway. How does one really compare Newton with Archimedes?

[ponchi101]

List of physicist:
Einstein
Newton
Rutherford
Lord Kelvin
Bohr
And then the usual suspects of modernity: Feynman, Weinberg, Higgs, etc.

You know who is missing from the math list? Gödel. He should be there. That Theorem of Incompleteness is way too important, both mathematically and philosophically.

[Suliso]

Any respectable list of physicists need to also include Planck, Schrödinger, Heisenberg and Maxwell. From modern ones probably only Feynman.

[skatingfan]

I'd like to take part in this conversation, but this is all I can add.