LC/MS/MS in Drug Development: Targeting the Brain

Success of drug development generally relies on selecting one or two most drug-like molecules from a large number of new chemical entities (NCEs) generated by combinatorial chemistry and subsequently filtered using in silico predictions. Drug-like properties include reliable bioactivity, favorable physical-chemical properties, and acceptable drug metabolism and pharmacokinetic (DMPK) profiles to enable “good” efficacy, availability, persistence, safety, and practicality in human (1). The use of highly sensitive and selective liquid chromatography tandem mass spectrometry (LC/MS/MS) assays during early in vitro and in vivo testing facilitates selection and advancement of one or two “best” compounds. Characterization of central nervous system (CNS) pharmacokinetics (PK), despite typically being performed during secondary or tertiary screening, is critical for the successful development of drugs targeting the CNS (e.g., anticonvulsants, antidepressants, anesthetics, antibacterials, and anticancer agents). The blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) represent the main anatomical and biochemical (structural or functional) barriers between the peripheral circulation and the CNS. Thus, a key issue during early stage CNS-targeted drug development is lead compound penetrability of the BBB and/or BCSFB. This review will provide an overview of the application of LC/MS/MS in the nonclinical development of CNS drugs.