Metabolites

Select Series 4 compounds were used to generate late-stage biofunctionalised metabolites using a range of liver microsomes and cytosols in a protocol run by Scott Obach at Pfizer. Four compounds were sent in 2017 with the following metabolites generated. Two metabolites were seen for MMV897709, but were not pursued further. Both amide compounds (MMV670246 and MMV670944) showed oxidation on the pyrazine ring and pyridine nitrogen respectively, but neither led to an improvement in potency. The benzylic primary alcohol MMV693155 generated a highly potent metabolite (link to OHOH campaign).

Another set of four compounds were evaluated in 2018, generating a new set of metabolites. Benyzlic hydroxy compounds MMV688896 and MMV672687 were both oxidised to the respective ketones and were not pursued further. Oxidation of the cubane in MMV1557938 led to two hydroxylated cubane isomers. Oxidation of the norbornene in MMV1557938 led to two mixtures (each with one epoxide and a cis and/or trans diol). All metabolites were found to be inactive at the tested concentrations.

Further compounds were proposed and sent in March-May 2018