Anthony A Paiva1, Cheryl Klakouski2, Shu Li1, Benjamin M Johnson2, Yue-Zhong Shu3, Jonathan Josephs4,5, Tatyana Zvyaga1, Ismael Zamora6, Wilson Z Shou1. 1. Bristol-Myers Squibb R & D, SATT, 5 Research Parkway, Wallingford, CT 06492, USA. 2. Bristol-Myers Squibb R & D, PCO, 5 Research Parkway, Wallingford, CT 06492, USA. 3. Bristol-Myers Squibb R & D, PCO, 3551 Lawrenceville, Princeton, NJ 08648, USA. 4. Bristol-Myers Squibb R & D, PCO, 311 Pennington Rocky Hill Road, Pennington, NJ 08534, USA. 5. Thermo Fisher Scientific, 355 River Oaks Parkway, San Jose, CA 95134, USA. 6. Lead Molecular Design SL, Sant Cugat de Valles, Spain.
Abstract
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.
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.
Authors: Daniel P O'Malley; Vijay Ahuja; Brian Fink; Carolyn Cao; Cindy Wang; Jesse Swanson; Susan Wee; Ashvinikumar V Gavai; John Tokarski; David Critton; Anthony A Paiva; Benjamin M Johnson; Nicolas Szapiel; Dianlin Xie Journal: ACS Med Chem Lett Date: 2019-09-25 Impact factor: 4.345