Lead Diversification

Superior Drug Derivatives via Late Stage Hydroxylation

There is increasing focus on thorough investigation of drug metabolites to identify derivatives that may have superior properties to the original drug. This is exemplified by Pfizer’s routine late stage lead diversification approach with screening of a lead compound in microsomal systems, which can then be subsequently scaled-up through chemical synthesis or microbial biotransformation to provide hundreds of milligrams of hydroxylated derivatives for evaluation of activity, solubility and metabolic stability. Hypha offers a flexible service in which hydroxylated products of drug leads can be generated, often via challenging modifications of unactivated C-H bonds. Read more on this in our newsletter on Superior drug derivatives via late stage hydroxylation.

Lead Compound Diversification and Late Stage Functionalization

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Our microbial panels not only mimic mammalian metabolism but have the added benefit of also producing other derivatives that might not have been considered or accessible using synthetic routes. The process is complementary to medicinal chemistry and can be exploited to diversify hit or lead compounds by generating oxidised molecules that may have greater activity, better selectivity or an improved availability profile than the parent molecule. It can also be used to help widen and protect IP and inform SAR. The technology can be applied at the lead optimisation stage or on compounds at earlier hit or hit-to-lead stages.

Late stage oxidation case study using PolyCYPs

In addition to our whole cell microbial biotransformation platform, we now have cloned enzymes, PolyCYPs®, capable of performing a wide variety of oxidation reactions. PolyCYPs enzymes are cloned from some of Hypha’s microbes talented at oxidising drug compounds, and come formatted in an easy-to-use screening kit for performing oxidation reactions in client labs.

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.

Hypha can also undertake a screening of drug compounds using PolyCYPs enzymes on behalf of a client. We offer a flexible end-to-end service including scale-up, purification and structure elucidation. Alternatively, scale-up reactions can be conducted at Hypha and products provided to the client for purification and structure elucidation.

Solve Excessive Lipophilicity

If you are looking to create more polar metabolites to improve solubility, we can apply our proven lipophilic rescue service to achieve improvement in LLE/LipE. The technology has the added benefit that multiple analogues can be produced in a single process. Selected derivatives can then be optimised and the production scaled-up.

Create Handles for Synthesis

Our process can create handles for further structural changes such as fluorination used for metabolism blocking or PET ligand formation.

Key features of our lead diversification service:

  • Flexible options – the process can be tailored to client needs
  • Provides a unique method for generating metabolites that are challenging to create synthetically
  • Scalable and reproducible process
  • Multiple metabolites can be captured in a single screen
  • Applicable to broad structural types and complex molecules, including natural products
  • Target molecules are produced at mg/g scale
  • Defined timelines and costs
  • Metabolites are produced on a simple fee-for-service basis, i.e. there are no downstream terms

Case Studies

Download our joint poster with Incyte on biological C-H activation of ruxolitinib to produce hydroxylated derivatives 

Download our poster on Microbial Hydroxylation of Lead Compounds: A Way Out of the Lipophilic Cul-de-Sac  a project conducted with Gilead and presented at the RICT Conference in France in 2014

Download a poster on Microbial Biotransformation as a Tool to Exploit the Potential of Drug Metabolites for Lead Optimization, presented at the Drug Discovery Chemistry Lead Optimization for Drug Metabolism and Safety meeting in San Diego in April 2018.

Download a copy of our poster with Astra Zeneca on Expanding chemical space via microbial late stage functionalization, presented at the RSC Medchem meeting in Hatfield UK in 2018.

Link to a Nature Reviews Drug Discovery paper on Expanding the medicinal chemistry synthetic toolbox. The paper by Bostrom et al., 2018 features examples of the outputs of Hypha’s hydroxylation technology. Hydroxylation is a key tactic to consider as part of a late stage functionalization strategy where small changes can result in improved activity, selectivity, solubility and lipophilicity.

Please contact us to discuss options.

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