Phosphine Oxides as Rising Stars in Drug Discovery

Phosphine oxides represent a noticeably underrepresented chemotype in drug discovery. However, the clinical validation of Brigatinib, containing dimethyl phosphine oxide, and the disclosure of other therapeutic preclinical compounds featuring these polar and hydrophilic functional groups have sparked a revived interest across the pharmaceutical sector. The surge in relevant publications have further highlighted an untapped potential in drug-like chemical space, as these analogues were shown to present beneficial physicochemical and ADMET properties. Phosphine oxides notably exhibit a highly polarized P=O bond, translating in enhanced hydrophilicity, and thus aqueous solubility and enhanced metabolic stability.

Acknowledging the current synthetic knowledge gap, enabling new synthetic methodologies to access this vastly uncharted chemical space is thus critical to capture the potential of phosphine oxides more extensively in drug design. This project will combine synthetic chemistry and ADME studies. Phosphine oxides motifs in new chemical space will be designed and prepared aiming to maximise the understanding of how this highly polar functional group can be best exploited in medicinal chemistry.