title: Restricting CNS penetration of drugs to minimise adverse events: role of drug transporters.
abstract: Some drug discovery approaches can benefit from restricting the access of compounds to the central nervous system (CNS) to minimise the risk of side-effects. Designing compounds that act as substrates for efflux transporters in the blood–brain barrier can achieve CNS restriction without significantly impairing absorption in the intestine. In vitro assays can be deployed to optimise a balance between passive permeability and active efflux via the ABC family transporters P-glycoprotein (P-gp, ABCB1) and Breast Cancer Resistance Protein (BCRP, ABCG2) whilst in vivo estimates of distribution of unbound concentrations of drug are needed to understand pharmacologically relevant exposure in peripheral and central compartments. This strategy can deliver significant CNS restriction whilst retaining good oral bioavailability, cell penetration and pharmacological activity. The possible risks of targeting P-gp and BCRP in orally delivered drugs are discussed.
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Neusentis, The Portway Building, Granta Park, Great, Abington, Cambridge, CB21 6GS, UK.
authors.forename: Sharan
authors.initials: S
authors.lastname: Bagal
authors.affiliation: Pfizer Neusentis, The Portway Building, Granta Park, Great Abington, Cambridge, CB21 6GS, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Bungay
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002199:Capillary Permeability; D055808:Drug Discovery / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000517:prevention & control*; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D018528:ATP-Binding Cassette Transporters; D004364:Pharmaceutical Preparations