[bearjaws]

This, I work in specialty pharmacies and Remdesivir is a complicated drug to produce.

Currently Gilead believe they can bring down their production time from 8-12 months 6-8 months, that means we won't see a large supply of this drug until 2021.

[throwaway_pdp09]

I have a noobish question. Looking at Remdesivir wiki page to try to get a feeling for why it's hard to make, their are some really odd chemicals used like this https://en.wikipedia.org/wiki/Trimethylsilyl_triflate

Why is something like this, with its silicon and sulphur atoms as part of the backbone, needed? Why wouldn't the same but with a more typical fully-carbon backbone work? If it's too complex a question, skip it, but thanks if you can shed light.

[alextheparrot]

The short “answer” is that the reaction step needs to form a carbon-carbon bond, which isn’t always trivial to make. A fully carbon backbone is likely not reactive in the way they need it to be here.

Certain “weird” metals like zinc, tin, and silicon (And these are the more normal ones) have been found to be able to help with this type of chemistry. The reason for why these metals are useful gets into orbital mechanics, but the core idea is that they can facilitate carbon-carbon bond formation.

The sulphur and fluorine are standard as part of the triflate functional group — it is a stable leaving group based on wanting electrons and being stable once it grabs those electrons (The sulphur can facilitate reasonable stabilisation).

[moonsu]

That compound in particular is used to help replace a C-OH bond with a C-CN bond. It may seem like a weird chemical but it's very commonly used in organic synthesis.

> Why wouldn't the same but with a more typical fully-carbon backbone work?

Because a fully carbon backbone would not be as reactive and would not attach/detach from the intermediate as needed

[basch]

I'm not even an armchair doctor, but is there any truth to it being overcomplicated in a way that offers no benefit in this specific situation? My incredibly lay interpretation of the article below is that Gilead purposely designed something much more complicated to synthesize, that ends up being less effective than its predecessor. It reads as if all the over engineering of Remdesivir ended up having no positive result.

https://www.statnews.com/2020/05/14/gilead-should-ditch-remd...

>The company has also developed GS-441524, another pro-drug that, as its name suggests, the body also converts into GS-441524 triphosphate, but in just in three steps. GS-441524 is easier to synthesize than remdesivir, requiring three steps instead of the seven needed for remdesivir.

>Researchers initially thought that remdesivir would be activated more quickly than GS-441524 in human cells infected with the SARS and MERS coronaviruses. Yet data from primary human airway epithelial cells — one of the most clinically relevant cell-based models of the human lung — showed no statistically significant difference in potency between the two compounds. When GS-441524 was used to treat cats with feline infectious peritonitis, a progressive and usually fatal disease caused by a coronavirus, it displayed remarkable safety and therapeutic efficacy, with 96% of cats recovering after treatment.

>Recent research in coronavirus-infected nonhuman primates demonstrated problems with remdesivir that inadvertently showed the antiviral effectiveness of GS-441524. In multiple studies testing remdesivir in coronavirus-infected mice or rhesus macaques, it was rapidly converted to GS-441524 in the bloodstream.

>Take the latest controlled study conducted in rhesus macaques infected with SARS-CoV-2: After remdesivir was administered intravenously, GS-441524 was present in serum samples at concentrations 1,000-fold greater than remdesivir. Upon completion of the study, the researchers found that only GS-441524 — not remdesivir — was detected in the macaques’ lungs, yet they exhibited no signs of respiratory disease, significantly reduced viral loads, and a distinct reduction in damage to lung tissue. Such results reinforce those obtained from a prior study, also in macaques, and data from other species that GS-441524 exhibits strong antiviral activity.

>The first step in the bioactivation of GS-441524 is the rate-limiting step, something that remdesivir was designed to avoid. But that doesn’t matter clinically because of remdesivir’s rapid transformation to GS-441524 in the bloodstream.

There is also a black market for GS-441524, which could be a reason Gilead doesnt want to promote it?

https://www.theatlantic.com/science/archive/2020/05/remdesiv...