title: Drug-like property profiling of novel neuroprotective compounds to treat acute ischemic stroke: guidelines to develop pleiotropic molecules.
abstract: The development of novel neuroprotective compounds to treat acute ischemic stroke (AIS) has been problematic and quite complicated, since many candidates that have been tested clinically lacked significant pleiotropic activity, were unable to effectively cross the blood brain barrier (BBB), had poor bioavailability or were toxic. Moreover, the compounds did not confer significant neuroprotection or clinical efficacy measured using standard behavioral endpoints, when studied in clinical trials in a heterogeneous population of stroke patients. To circumvent some of the drug development problems describe above, we have used a rational funnel approach to identify and develop promising candidates. Using a step-wise approach, we have identified a series of compounds based upon two different neuroprotection assays. We have then taken the candidates and determined their "drug-like" properties. This guidelines article details in vitro screening assays used to show pleiotropic activity of a series of novel compounds; including enhanced neuroprotective activity compared to the parent compound fisetin. Moreover, for preliminary drug de-risking or risk reduction during development, we used compound assessment in the CeeTox assay, ADME toxicity using the AMES test for genotoxicity and interaction with Cytochrome P450 using CYP450 inhibition analysis against a spectrum of CYP450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) as a measure of drug interaction. Moreover, the compounds have been studied using a transfected Madin Darby canine kidney (MDCK) cell assay to assess blood brain barrier penetration (BBB). Using this series of assays, we have identified 4 novel molecules to be developed as an AIS treatment.
authors.affiliation: Director of Translational Research, Cedars-Sinai Medical Center, Department of Neurology, Davis Research Building, D-2091, 110 N. George Burns Road, Los Angeles, CA 90048 USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Lapchak
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000378:metabolism; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D003584:Cytological Techniques; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods; D005419:Flavonoids / Q000493:pharmacokinetics / Q000627:therapeutic use; D044948:Flavonols; D006801:Humans; D009152:Mutagenicity Tests / Q000379:methods; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D017410:Practice Guidelines as Topic; D020521:Stroke / Q000188:drug therapy*
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D005419:Flavonoids; D044948:Flavonols; D018696:Neuroprotective Agents; C017875:fisetin
keywords: ADME; Ames test; MDCK; chalcone; flavone; flavonoid; pleiotropic; screening; toxicity