Discovery of a New Chemical Series Based on Metabolic Rearrangement

Surprising biotransformation leading to active metabolite

The structure elucidation and biological testing of metabolites can allow for discovery of new chemical entities.

In their CB1 therapeutic program, Dr Chien-Huang Wu et al. discovered the formation of a unique metabolite resulting from a biotransformation of their lead compound 1. Surprisingly, the imide moity of that molecule undergoes metabolic N-demethylation to form the intermediate 2. This compound rearranges by cyclization to generate the imidazole-4-one 3. More interestingly, the resulting compound showed potency and was used as a starting point to develop a new chemical series. The metabolite isolation allowed for the discovery of a new chemical series.

J. Med. Chem. 2009, 52, 4496-4510