‘Impossible’ synthesis and drug manufacture to treat rare disease

2024-03-26T05:58:32+13:002 June 2022|Tags: |
Rare genetic disorders affecting a small number of people can have a devastating impact on their lives. For instance, one such disorder causes a deficiency that leads to brain damage and eventual death in young people. In 2010, a client approached GlycoSyn and the Ferrier Research Institute seeking a therapy that could use a synthetic replacement for the missing compound.

Proven activity on a trial scale

The therapy had previously been isolated from bacteria and had proven activity in mice. Producing the compound in larger quantities was a logical next step, but the fearsomely complex molecule had never been made synthetically before. Therefore, discovery chemistry and chemical process engineering were paramount to getting a treatment into the clinic

“Our client came to us knowing the product would work but they had to find a way to synthesise it”, says Dr Paul Benjes.

Next steps in the lab

“The compound had been made by microbial fermentation before but the yield was so low that it would never have been viable as a commercial manufacturing technology. The client spoke to multiple companies to develop a laboratory method, but we were the only ones who were able to make it.”

GlycoSyn drug discovery chemists used a particular and little-known reaction to produce a critical intermediate en route to the product. But overall it was far from easy.

“It’s really hard chemistry, there is tricky stereochemistry, several cyclic elements and the potential for the product to be unstable. We were lucky to find a way to make an intermediate with the chiral centers in place, and then get it out quite cleanly through crystallisation.

Large scale manufacturing and analysis

Most of the initial route development work was done in collaboration with our joint venture partners at the Ferrier Research Institute. The project transitioned to GlycoSyn’s scale up facilities once a workable process had been achieved. It was then refined and optimised through process chemistry for large-scale production. Quality specifications for the intermediates and final product were developed, which lead to eventual  GMP manufacture.

Analytical research was also required to develop new methods to assay the product because of its propensity to oxidise during analysis.

“Without the analytical method development we were able to do in-house, it would have been really hard to find a way to create a viable specification for the compound.”

Eventually multiple batches of several hundred grams were made at GlycoSyn under current Good Manufacturing Practices. This material was used for safety studies and clinical trials.

More information

Keith Clinch, Derek K. Watt, Rachel A. Dixon, Sylvia M. Baars, Graeme J. Gainsford, Ashish Tiwari, Günter Schwarz, Yas Saotome, Michael Storek, Abdel A. Belaidi & Jose A. Santamaria Araujo (2013). Synthesis of Cyclic Pyranopterin Monophosphate, a Biosynthetic Intermediate in the Molybdenum Cofactor Pathway. Journal of Medicinal Chemistry. 56: 1730-1738, doi:10.1021/jm301855r.

Graeme J. Gainsford, Keith Clinch, Rachel Dixon & Ashish Tiwari (2012). tert-Butyl (2R,4aR,5aR,11aS,12R,12aR)-8-[bis(tert-butoxycarbonyl)amino]-12-hydroxy-2-methoxy-2,10-dioxo-4,4a,5a,6,9,10,11,11a,12,12a-decahydro-2H-1,3,5-trioxa-6,7,9,11-tetraaza-2λ-phosphatetracene-6-carboxylate methanol monosolvate monohydrate. Acta Crystallographica. 68E. o2250-2251, doi: 10.1107/s160053681202867x.

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