S141: Drug metabolite synthesis with biocatalysts-challenge, strategy and impact

Metabolite characterization is an important part of drug discovery and development process, which often involves synthesis of key metabolites for structure elucidation, biological activity evaluation, and use as analytical standard. Challenges for metabolite synthesis arise from several fronts 1) the exact structure of the metabolite of interest is often not known; 2) some metabolites are difficult to prepare and/or not stable; 3) short timeline. Complementary to chemical synthesis, biosynthesis of drug metabolites with mammalian or microbial biocatalysts offers certain advantages, and sometime is the only practical route to the desired metabolite. Thus, a tiered approach was adopted for synthesis of difficult metabolite: 1) preparing a limited amount using mammalian system for structure elucidation or acquiring analytical data; 2) generating larger amount using microbial system for biological activity evaluation and use as analytical standard; 3) employing a suitable method (microbial, recombinant CYP enzyme or chemical synthesis, based on feasibility and efficiency) to meet the further needs. This presentation will focus on biosynthesis of oxidative and glucuronide metabolites. Examples will be discussed to illustrate the approach and its impact on drug discovery and development projects