Charles John O'donnell

A matched molecular pair analysis of in vitro human microsomal metabolic stability measurements for heterocyclic replacements of di-substituted benzene containing compounds – identification of those isosteres more likely to have beneficial effects

A matched molecular pair analysis (MMPA) was used to study the classic medicinal chemistry transformation of a di-substituted benzene into a heterocyclic ring. Matched pairs were identified for 45 heterocyclic transforms (5 and 6 membered rings) and in vitro human microsomal stability analysed. Of these, 12 transforms showed significant beneficial increase in stability, suggesting these heterocycles as preferred changes during compound optimisation.

Optimisation of biphenyl acetic acid inhibitors of diacylglycerol acetyl transferase 1 – the discovery of AZD2353

Inhibition of diacylglycerol acetyl transferase 1 is of great interest in the treatment of diabetes, obesity and other diseases that constitute the metabolic syndrome. Small molecule inhibitors of the enzyme are often dogged with physicochemical property-related problems such as poor solubility. Herein, the optimisation of a series of biphenyl acetic acid inhibitors is reported. Focus on ligand efficiency and ligand lipophilicity efficiency and a strategy based on conformational restriction led to compounds with excellent potency and ADMET properties, culminating in the discovery of AZD2353.