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The Story behind the discovery of FV100, a potent anti-shingles drug

Sonsoles Velazquez

Sonsoles Velázquez

 

In January 1995, Sonsoles Velázquez, a Postdoctoral fellow working in Prof Chris McGuigan’s lab at the Welsh School of Pharmacy prepared some 5-alkynyl-2’-deoxyuridines, such as the decynyl compound Cf904 shown here:

structure of Cf904 prototype anti-shingles drug

 

 

Jan Balzarini

Jan Balzarini

The compound was prepared as a synthetic starting material in an HIV programme.  It was not intended to be active but was sent to our collaborators in Leuven, Belgium for antiviral assay as a ‘negative control’.  Our lead collaborator in Leuven, Dr Jan Balzarini, had the foresight to test Cf904 against a broad range of DNA (and RNA) viruses and – surprisingly – found it to be rather active against VZV, the chickenpox-shingles virus. 

We were surprised by this result as previous compounds similar to 904 had been tested against these viruses and found to be inactive.  So we re-prepared Cf904 and re-shipped it.  This time it came back inactive; when we re-prepared it a 3rd time it was still inactive.  Indeed when all 3 ‘identical’ samples of Cf904 were tested side by side in Leuven the first batch remained active.  It was equi-active with acyclovir, the drug of choice, at about 1µM versus VZV.  All 3 batches had been examined by spectroscopic and analytical methods in Cardiff before shipping and they were all pure and identical, so there was no easy explanation for the difference in their biological activity. 

At this point, Leuven re-shipped the 3 batches back to Cardiff.  Less than 1mg of the active batch remained, hence our ability to examine the batches was limited.  But, when studying them by a simple TLC test we saw that batch 1, the active batch, contained a small (ca. 1%) fluorescent impurity.  We reasoned that this must have been responsible for the activity observed in batch 1.

 

structure of Cf1368 prototype anti-shingles drug

This impurity could not have been in the sample when it left Cardiff as it would have shown up in our earlier analysis.  So how and where did it arise?  With the tiny amount of batch 1 remaining we were able to isolate a fraction of a mg of pure contaminant and run a mass spectrum to determine its molecular mass.  Remarkably this revealed the same molecular weight as Cf904.  So the (active) impurity was an isomer (due to ring closure) of the intended product, that was absent when shipped but arose in the mail or storage in Leuven prior to assay. 

 

Gary Jones

Gary Jones

Realising that a 1% sample of this new compound was equi-active with acyclovir, the drug of choice for VZV, we set to work to prepare the ‘impurity’ in a pure state.  

Gary Jones first prepared the compound Cf1368 on 20th November 1996, and on testing in Leuven it was found to be 360 times more potent than acyclovir against VZV.  Then we pursued Cf1368 extensively and realised this represented an entirely new family of antiviral, we named them the BCNAs (Bicyclic Nucleoside Analogues). Cf1368 represented our initial ‘hit’ in this series; we suspected we could tune its structure to improve its activity and that’s what we did.

 

 

structure of Cf1743 anti-shingles drug

 

Hubert Barucki

Hubert Barucki

In 1999 Hubert Barucki of our lab prepared an aromatic analogue of Cf1368, known as Cf1743 which emerged as exquisitely potent and selective against VZV.   This family of molecules was patented by us and subsequently licensed to New York start-up company Fermavir (CEO Dr Geoff Henson). 

Working closely with Fermavir we discovered that the very low water solubility of Cf1743 would create a problem with dosing to patients so we worked with Leuven as well as Maria-Jose Camarasa and Sonsoles Velázquez at CSIC in Madrid to produce an oral ProDrug FV100.     Fermavir subsequently merged with Inhibitex GA.

 

Geoff Henson

Geoff Henson

 

Maria-Jose Camarasa

Maria-Jose Camarasa

 

 

structure of FV-100 anti-shingles drug

 

This compounded entered Phase 1 clinical trials sponsored by Inhibitex GA on October 24th 2007 and successfully completed this safety study in 2008.  In May 2009 Inhibitex launched a major 50-centre double-blind controlled trial of FV100 versus valacyclovir (a pro-drug of acyclovir), the current standard of care, in VZV shingles patients.  This trial should conclude in 2010 and will show if FV100 out performs the current treatments for VZV.  If successful, a larger, phase 3 trial will be established prior to seeking approval to market the drug.  

 

Prof. Chris McGuigan

Prof. Chris McGuigan

Inhibitex Team with Prof McGuigan

Inhibitex Team with Prof McGuigan

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Prof Chris McGuigan

Position:Professor of Medicinal Chemistry
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