Lead optimization attrition analysis (LOAA): a novel and general methodology for medicinal chemistry

•Attrition rate difference not readily anticipated based on individual parameters.•Differentiation of series was significant when ADME parameters were included.•Percentage versus compound numbers meeting criteria provided graphical overview.•Steep decline (0 of 493 compounds) meeting 17/28 parameters – Series A fragile.•Shallow decline (21 of 504 compounds) meeting 17/28 parameters – Series B robust. Herein, we report a novel and general method, lead optimization attrition analysis (LOAA), to benchmark two distinct small-molecule lead series using a relatively unbiased, simple technique and commercially available software. We illustrate this approach with data collected during lead optimization of two independent oncology programs as a case study. Easily generated graphics and attrition curves enabled us to calibrate progress and support go/no go decisions on each program. We believe that this data-driven technique could be used broadly by medicinal chemists and management to guide strategic decisions during drug discovery.