A key strategic imperative of research and medicinal chemistry is designing molecules that survive to achieve positive proof of mechanisms. Several in vitro cell-based assays to assess blood brain barrier (BBB) permeability exist. Useful high-throughput assays have been developed employing cell lines such as MDCK stably transfected with the human multidrug resistance 1 (MDR1) p-glycoprotein (P-gp). Based on the prominent of P-gp in efflux mechanisms at the BBB, these assays have been instrumental in lead development for optimizing brain permeability. One strategy to avoid P-gp and optimize brain availability of drug candidates is to understand how physicochemical properties impact P-gp liability and passive permeability. Advances in prospective design include the development of a novel approaches to assess drug-likeness. A new multi-parameter design tool (CNS MPO Desirability) focuses on a holistic approach to drug discovery and aims to align drug-like attributes such as low P-gp liability, low metabolic clearance, high passive permeability and safety in one molecule. Examination of the desirability approach to CNS Oncology drug discovery will be presented, including: case studies of past oncology and CNS drugs.

Targeting CNS availability for oncology: Role of P-gp, BCRP, and CNS MPO desirability in CNS drug discovery

247th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.