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