Understanding the fate of your lead compound can help you to design your drug candidate. In the following example Fujimoto et al. (J. Med. Chem., 2010, 53 (9), 3517-3531) after elucidation of an active minor metabolite, designed a compound that blocked the main metabolism pathway, a hydrolysis.
In the course of their FXa inhibitor drug discovery program, the authors were able to optimize the properties of their previous best compound 1 by blocking the site of amide bond hydrolysis. Indeed, compound 2 was identified as the main metabolite of compound 1 in human microsome but not in monkey. This difference made pharmacokinetic properties difficult to be predicted in human based on monkey studies. To minimize this issue the authors focused on finding new FXa inhibitors with improved stability toward hydrolysis. Metabolism studies of compound 1 showed the formation of an active minor metabolite resulting from hydroxylation, the compound 3. Additionnally, this compound showed significant decrease in hydrolysis to compound 2 in human microsome. This could resolve the issue of pharmacokinetic prediction using monkey data. Drug design work around compound 3 allowed the authors to find a clinical candidate 4 with better pharmacokinetic properties. Basaed on this example, we believe that novel approaches to synthesize metabolites are now absolutely required to better optimize lead compounds. The HepatoChem Technology platform affords such an opportunity by allowing rapid access to metabolites directly from the compound of interest in a biomimetic fashion.