Central Nervous System Multiparameter Optimization

ALAN TALEVI

The ADME Encyclopedia. A Comprehensive Guide on Biopharmacy and Pharmacokinetics

Springer Nature

Año: 2022; p. 242 - 249

The Central Nervous System Multiparameter Optimization (CNS-MPO) desirability score is a composite score conceived at Pfizer, to assist drug discovery of therapeutic agents targeting central nervous system (CNS) conditions [1, 2]. The general idea is to delimitate a region of the chemical space possessing alignment of key properties for CNS therapeutic agents: high passive permeability, low unbound intrinsic clearance, low P-glycoprotein (P-gp) efflux liability, low CYP3A4 and CYP2D6 interactions, low hERG liability and low cytotoxicity [2, 3]. The desirability score for a given CNS drug candidate is obtained by summating individual components associated to six key physicochemical properties related to drug-likeness. These are: molecular weight (MW), topological polar surface area (TPSA), pKa of the most basic center / ionizable function, calculated octanol-water partition coefficient (ClogP), calculated distribution coefficient at pH = 7.4 (clogD) and the number of hydrogen bond donors (HBD).