Gilead’s innovative approach to Hep C drug, Sovaldi

Hepatitis C virus (HCV) is a single-stranded RNA virus that infects an estimated 180 million people worldwide.

In 2013, Gilead received FDA approval for a new HCV drug, Sovaldi (sofosbuvir), that inhibits viral replication by targeting the virus’s NS5B polymerase.  Sovaldi has shown a very high cure rate (nearly 100% HCV suppression and sustained virological response) in clinical trials of previously untreated patients and has fewer side effects than pegylated-interferon and ribavirin therapies.

Sovaldi is a methyluridine-monophosphate prodrug: it is metabolized in the body back into methyluridine-triphosphate, which acts as a potent substrate mimic and inhibitor of the NS5B polymerase.

What is interesting about Sovaldi is the approach the scientists took to getting the inhibitor into the cell, relying on phosphoramidate prodrug  technology that had been effectively used to develop anti-HIV drugs, but had never been applied before to this class of anti-HCV drugs.

During development, the researchers decided that they needed to deliver the charged methyluridine-monophosphate (rather than the neutral methyluridine)  into the cell on the basis of two key observations:  1) the methyluridine triphosphate is the active compound against HCV NS5B polymerase, while the methyluridine alone is inactive (owing  to very low conversion to monophosphate in vivo) and 2) the methyuridine monophosphated derivative can be anabolized in the cell back to the potent triphosphate form by an endogenous uridine-cytidine monophosphate kinase.

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The active uridine triphosphate (6) can be created when 4 is metabolized to methyluridine-5′-monophosphate. Compound 5 is not phosphorylated and is inactive in cells.

 

The phosphoramidate prodrug technology had never been applied to HCV inhibition until Solvadi.

The idea behind  phosphoramidate prodrug technology is to create a membrane-soluble neutral prodrug derivative that can be metabolized in the liver by carboxylesterase-mediated cleavage and subsequent steps back to the monophosphate form.

The researchers applied the approach and after a significant amount of  SAR investigation and PK/PD studies around the chemical composition of the phosphoramide substituents, they concluded that the structure of compound shown above was the optimal structure to deliver the methyluridine-monophosphate to the liver.

The result is a new generation of highly effective HCV therapeutics with few side effects that can make a significant difference in the lives of patients living with HCV.

 

Why are many drugs aromatic heterocycles?

To the non-specialist in medicinal chemistry (like myself), the abundance of drugs that contain aromatic ring moieties, usually with heteroatoms like N, is somewhat surprising. In fact, in 2012, the top 4 out of 5 drugs by sales contain such groups. 

There are at least a few good reasons why these types of compounds appear so often:

1 Heterocyclic systems are easier to prepare synthetically than all-carbon based aromatic systems and they are easier to modify later.

2  Scaffolds with heterocycles allow the easy introduction of H-bond donors and acceptors to fine-tune the properties of the compound, like binding affinity, solubility, and resistance to metabolism in vivo.

3 Can “template hop” easily off of aromatic ring scaffolds to evolve new IP with the same functionality as a known drug (e.g., Viagra to Levitra).

Can synthetic chemistry specialists give more reasons?  (Post in the comments!) 

Source:  Jordan, A, Roughley, S.  “Drug discovery chemistry: a primer for the non-specialist.”  Drug Disc Today, 14. 2009