title: Strategies to minimize CNS toxicity: in vitro high-throughput assays and computational modeling.
abstract: BACKGROUND
  Healthy functioning of the brain is dependent on the ability of the blood-brain barrier (BBB) and other central nervous system (CNS) barriers to protect the neurocompartments from potential disruptive and damaging xenobiotic agents. In vitro high-throughput (HT) screens and computational models that assess a compound's ability to pass through or disrupt the BBB have become important tools in the identification of new well-tolerated peripheral drugs and safer chemical products such as pesticides. Leveraging these HT in vitro assays and computational BBB tools together with the current understanding of brain penetration may enable the drug discovery community to minimize access of drug candidates into the CNS compartment.
  
  
  METHODS
  This article reviews aspects of the most recent in vitro and computational approaches designed to provide an early assessment of a compound's ability to access the neurocompartment. This article also provides insight into using these tools to identify compounds that have restricted access to the neurocompartment.
  
  
  CONCLUSIONS
  The development of safer peripheral-acting medicines and chemical products can be achieved through prospective design and early assessment with HT assays of the BBB in conjunction with computational models. Exclusion or significantly reduced access of a compound to the neurocompartment will increase the odds of identifying a compound with reduced CNS-related adverse drug reactions. A holistic approach to compound design and evaluation that incorporates prospective design principles (e.g., optimization of physicochemical properties), leverages HT in vitro assays and integrates the use of BBB computational models may yield the 'best-in-class' peripherally acting product.
authors.affiliation: Pfizer, Worldwide Research and Development, Eastern Point Road, Groton, CT, USA. travis.t.wager@pfizer.com
authors.forename: Travis T
authors.initials: TT
authors.lastname: Wager
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Liras
authors.forename: Scot
authors.initials: S
authors.lastname: Mente
authors.forename: Patrick
authors.initials: P
authors.lastname: Trapa
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects* / Q000473:pathology*; D055598:Chemical Phenomena; D003198:Computer Simulation; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D010599:Pharmacokinetics
chemical_list: D018528:ATP-Binding Cassette Transporters