Identification of Isoform 2 Acid-Sensing Ion Channel Inhibitors as Tool Compounds for Target Validation Studies in CNS
By Bencheva Leda Ivanova; De Matteo Marilenia; Ferrante Luca; Ferrara Marco; Prandi Adolfo; Randazzo Pietro;…
By Di Marco, Annalise; Gonzalez Paz, Odalys; Fini, Ivan; Vignone, Domenico; Cellucci, Antonella; Battista, Maria Rosaria; Auciello, Giulio; Orsatti, Laura; Zini, Matteo; Monteagudo, Edith; et al
From Molecular Pharmaceutics (2019), 16(5), 2069-2082. Language: English, Database: CAPLUS, DOI:10.1021/acs.molpharmaceut.9b00042
Huntington’s disease (HD) is a neurodegenerative disease caused by a polyglutamine expansion in the Huntington (HTT) protein. For drug candidates targeting HD, the ability to cross the blood brain barrier (BBB) and reach the site of action in the central nervous system (CNS) is crucial for achieving pharmacol. activity. To assess permeability of selected compds. across the BBB, we utilized a two-dimensional model composed of primary porcine brain endothelial cells and rat astrocytes. Our objective was to use this in vitro model to rank and prioritize compds. for in vivo pharmacokinetic and brain penetration studies. The model was first characterized using a set of validation markers chosen based on their functional importance at the BBB. It was shown to fulfill the major BBB characteristics, including functional tight junctions, high transendothelial elec. resistance (TEER), expression and activity of influx and efflux transporters. The in vitro permeability of fifty-four, structurally diverse, known compds. was detd. and shown to have a good correlation with the in situ brain perfusion data in rodents. We used this model to investigate BBB permeability of a series of new HD compds. from different chem. classes and we found good correlation with in vivo brain permeation, demonstrating the usefulness of the in vitro model for optimizing CNS drug properties and for guiding the selection of lead compds. in a drug discovery setting.