Late Stage Oxidation using PolyCYPs enzymes – PolarExplorer

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PolarExplorer – Late stage hydroxylation using PolyCYPs enzymes

Small changes to a structure through late stage functionalisation can have a large impact in achieving improved LLE and solubility of drugs. Hydroxyl groups are the most common functional group in drugs and can reduce clogP by >1 unit, as well as enhance metabolic stability. Other benefits such as increased potency and greater selectivity are also achievable through late stage hydroxylation.

Hypha’s PolyCYPs® enzymes provide a fast and easy way to hydroxylate aliphatic or aromatic moieties at multiple sites in parallel, including metabolically susceptible positions. Both CYP-derived human metabolites and other oxidised derivatives can then be accessed simultaneously for structure elucidation and biological testing.

PolyCYPs® enzymes in the kit have been cloned from some of the talented actinomycete bacteria in Hypha’s biotransformation panel, providing a wide diversity of CYPs that hydroxylate a variety of drug compounds.

 Lead diversification case study

In this case study, five active monohydroxylated derivatives of a client’s drug lead were produced using PolyCYPs, with a 56% conversion of the parent drug by the best PolyCYP enzyme, enabling access to polar chemical space in parallel as part of SAR studies. Access a pdf of the poster on “Late Stage Functionalization of Drug Candidates using PolyCYPS® Enzymes” here.

PolarExplorer process

Drug candidates are screened in client labs against PolyCYPs enzymes in the screening kit to identify isoforms undertaking the desired oxidation(s). For lipophilic compounds, a cyclodextrin-based formulation reagent is included to aid solubilisation. Scale-up vials of any specific isoform can then be ordered to generate more material for further testing.

This process can also be operated at Hypha as a service option if preferred, as undertaken for a number of European and US Pharma companies.

Client Feedback for PolarExplorer Service

“We would like to mention that it has been a pleasure to work with Hypha in this project. We are really satisfied with how the collaboration has progressed, reaching the defined goals and timelines in a very efficient manner. Access of hydroxylated compounds through PolyCYPs has saved our company time and resources. We are sure that we will have more opportunities to work together in the future.”

Program Leader, European Pharma Company

“The services conducted by Hypha allowed Alkermes to enhance our “Late Stage Functionalization” efforts to rapidly expand our SAR understanding inside projects. In particular, the PolarExplorer work allowed facile generation of hydroxylated compounds possessing a complex molecular core.
We look forward to engaging Hypha in the future because their team is professional, and their services complement our internal synthetic efforts for delivering new molecules.”

Brian Aquila, Director of Medicinal Chemistry, Alkermes, Waltham MA, USA

For more information or to order a kit, email enquiries@hyphadiscovery.co.uk

Download a pdf of the PolyCYPs brochure here.

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