Development, optimization and implementation of a centralized metabolic soft spot assay.

Aim: High clearance is a commonly encountered issue in drug discovery. Here we present a centralized metabolic soft spot identification assay with adequate capacity and turnaround time to support the metabolic optimization needs of an entire discovery organization.

Methodology: An integrated quan/qual approach utilizing both an orthogonal sample-pooling methodology and software-assisted structure elucidation was developed to enable the assay. Major metabolic soft spots in liver microsomes (rodent and human) were generated in a batch mode, along with kinetics of parent disappearance and metabolite formation, typically within 1 week of incubation.

Results & Conclusion: A centralized metabolic soft spot identification assay has been developed and has successfully impacted discovery project teams in mitigating instability and establishing potential structure-metabolism relationships.