Should Medicinal Chemists Dread Phosphine Oxides?

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At Charnwood Discovery we are always looking to employ innovative strategies to solve problems in drug discovery and development

In this blog Senior Research Chemist II, Dr Rhydian Beddoe share’s his thoughts on a recent paper published on the use of phosphine oxides as a useful drug design motif.

The phosphine oxide is a functional group that will often bring about feelings of dread to a medicinal chemist. It is most often encountered as triphenylphosphine oxide – a by-product produced in many phosphorus-mediated chemical reactions, which is notorious for being difficult to remove from a crude reaction mixture.

However, phosphine oxides are also valuable, yet underutilised, structural motifs in drug design. They consist of one short, polar P=O, and three P–C bonds, which are approximately 20% longer than analogous C–C bonds. The functional group can be broadly characterised as a highly polar, stable, and neutral at physiological pH.

In a recent study (J. Med. Chem. 2020, 63, 7081-7107) Gamm and co-workers conducted a systematic evaluation of the physicochemical properties of imatinib analogues, modified with phosphine oxides and other phosphorus-containing functional groups.

They also explored how these imatinib analogues behaved in typical in vitro permeability and microsomal stability assays. They found that the incorporation of phosphine oxides into the compound scaffold resulted in decreased lipophilicity and increased solubility. Phosphine oxides were also found to be stable in liver microsomes without revealing any intrinsic metabolic ‘hotspots.’ One potential liability noted is that phosphine oxide-containing compounds can suffer from poor permeability, due to their high polarities.

There are numerous robust methods reported for synthesising phosphine oxides, (See Curr. Org. Chem. 2007, 4, 31–45 or Chem. Rev. 1960, 60, 243–260). We have recently made a series of phosphine oxide-containing compounds to support one of our client’s drug discovery programs.

Since the incorporation of phosphine oxides allows for the fine-tuning of physicochemical properties, without the introduction of metabolic liabilities, it is a strategy that we will be keen to employ on future drug discovery projects.

Find out more about our synthetic and medicinal chemistry services.

A bit about the Author

Dr Rhydian Beddoe is a Senior Research Chemist II in the Medicinal Chemistry department at Charnwood Discovery. His PhD was obtained at the University of Nottingham, which was focused on the development of phosphine oxide-catalyzed processes in organic chemistry.

Prior to working at Charnwood Discovery, he worked at Evotec as a medicinal chemist and has worked across a variety of drug discovery programs across multiple disease areas throughout his career.

In his spare time, Rhydian enjoys cycling and running and likes to take part in Nottingham’s annual Robin Hood half marathon.

You can connect with Rhydian on LinkedIn here.