PROCESS DEVELOPMENT
Cardiff University. The McGuigan group have developed two anti-viral nucleoside analogues that have progressed through to human trials in collaboration with US company Inhibitex. One of these, INX-189, which is active against hepatitis C, is the first example of the ‘Pro- Tide’ concept. This involves enhancing the nucleoside drug by phosphorylation and then masking the phosphate to aid transport through the cell wall. The strategy Pfizer was developing in collaboration with Peakdale involved the deployment of phosphonic acids as relatively stable analogues of nucleoside monophosphates. These can still undergo phosphorylation and generate effective nucleoside triphosphate mimics. The flexible route Peakdale developed to these targets is outlined in Fig 4.5 The key step in the sequence is the Arbuzov reaction from iodide 10 using diisopropyl phosphonate as the phosphorus source.
Keys to success “As with any research projects sometimes progress is fast, sometimes it stalls,” says Wainwright. “This is when the working relationship between the customer and their chosen CRO partner is crucial. It is our experience that good communication and earning the trust of our customers are key to a successful collaboration. The progress of this project was monitored with regular teleconferences with Pfizer personnel, and this
allowed for a collaborative approach as both organisations worked together to solve problems. This was complemented by regular face-to-face meetings to evaluate the service, review the science and, if necessary, replace intractable targets with alternatives. The metric data were also reviewed to ensure Pfizer received the numbers they were looking for.”
This fledgling FTE project was Peakdale’s first taste of taking on the challenge of running a chemistry project team for a customer, a business model that is now commonplace just a few years later, and for both companies the project was a success: “This resulted in a library of nucleosides for Pfizer for active research projects, as well as a legacy for years to come,” comments Wainwright. “We were fortunate that some of the novel chemistry generated has since been published, which is relatively rare for a CRO to be allowed to do. It is very satisfying for our scientists to be able to share our work with the wider scientific community. This was a very enjoyable project to work on, from the science and the challenges it presented, through to the work environment and the collaboration with Pfizer personnel.” In 2010, just a few years since the start of
Peakdale’s first FTE project, the company expanded with the opening of a facility operating from the Pfizer Research site in Sandwich, UK, which involved building up to a team of more than 50 synthetic chemists at the facility. Peakdale now operates out of this Discovery Park and offers a range of specialist services, including high throughput automated chromatography, high pressure
Meet Mark Betson and Phil Wainwright of Peakdale Molecular
Dr Mark Betson has been with Peakdale Molecular since 2005 where he is currently employed as a Group Leader. During this time he has had experience of leading a wide variety of chemistry projects for both major pharmaceutical customers and smaller biotechs. He started his chemistry career at the University of Manchester where he received a First Class Honours Degree in Chemistry in 1998 and went on to obtain a PhD from the University of Cambridge under the supervision of Professor Ian Fleming, studying the relative importance of steric and electronic influences in diastereoselective reactions. He subsequently returned to Manchester to work with Professor Jonathan Clayden as a Postdoctoral Research Assistant for three years before joining Peakdale. He is also currently a member of the SCI’s Young Chemists Panel.
Dr Phil Wainwright completed his PhD at the University of Salford under the supervision of Professor Barry Lygo, working in the field of asymmetric phase-transfer catalysis. He then moved in 1997 to his first industrial post at Amersham International (now Quotient) in Cardiff carrying out carbon-14 custom preparations. In 2002, he moved to Peakdale Molecular as a Technical Manager and soon after starting was responsible for the Pfizer nucleosides project. He is currently a Research Leader at Peakdale, and is still active in the field of nucleosides and nucleotides as well as promoting Peakdale’s scientific standards and expertise both internally and externally.
22 sp2 Inter-Active July/August 2012
chemistry and medicinal chemistry services. The company’s headquarters at Chapel-en-le- Frith continues to offer its synthetic and medicinal chemistry services, in-vitro ADMET services, organic materials research and nucleoside research services.
REFERENCES
1. “Outsourcing Lead Optimization: The Eye of the Storm”; D. E. Clark, Drug Discovery Today, 2011, 16, 3/4, 147.
2. “Stereoselective Synthesis of rac-4’- Ethynyl-2’,3’-dideoxy-2’,3’- didehydronucleoside Analogues”; P. Wainwright, R. Glen, R. Fisher, P. S. Dragovich, J. Gonzalez, P.-P. Kung, D. S. Middleton, D. C. Pryde, P. S. Stephenson and S. C. Sutton, Synthesis, 2007, 9, 1378; “Synthesis of Enantiomerically Pure 4- Substituted Riboses”; A. Maddaford, T. Guyot, D. Leese, R. Glen, J. Hart, X. Zhang, R. Fisher, D. S. Middleton, C. L. Doherty, N. N. Smith, D. C. Pryde and S. C. Sutton, Synlett, 2007, 20, 3149.
3. “Practical Synthetic Routes to Carbon- substituted Nucleosides”; D. C. Pryde, D. S. Middleton, P. T. Stephenson, P. Wainwright, A. Maddaford, X. Zhang, D. Leese, R. Glen, J. Hart, N. Forrest and T. Guyot, Tetrahedron Lett., 2011, 52, 6415.
4. “Synthesis of Novel 2-cyano-7-deaza-8- azapurine and 2-cyano-8-azapurine derived nucleosides”; P. Wainwright, A. Maddaford, M. Simms, X. Zhang, D. Lees, R. Glen, J. Hart, N. Forrest, D.C. Pryde, D.S. Middleton, P.T. Stephenson, T. Guyot, S.C. Sutton, Synlett, 2011, 1900 5. “A Flexible, Efficient Synthesis of (±)- Carbocyclic Phosphonic Acid Nucleoside Derivatives”; A. Maddaford, R. Bissell, R. Fisher, D. Leese, A. Lund, K. Runcie, P. S. Dragovich, J. Gonzalez, P.-P. Kung, D. S. Middleton, D. C. Pryde, P. T. Stephenson and S. C. Sutton, Synlett, 2005, 5, 765.
This article is by Dr Mark Betson, with additional comments from Dr Phil Wainwright, both of Peakdale Molecular.
Further information Dr Mark Betson Peakdale Science Park Sheffield Road Chapel-en-le-Frith High Peak Derbyshire SK23 0PG United Kingdom Tel: +44 1298 816700 Fax: +44 1298 816701
Internet links: Email:
mark.betson@
peakdale.co.uk Web:
www.peakdale.co.uk
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44