naa a22 4500 510775926 CHVBK 20180411083230.0 cr unu---uuuuu 180411e20130601xx s 000 0 eng 10.1007/s12975-012-0200-y doi (NATIONALLICENCE)springer-10.1007/s12975-012-0200-y Lapchak Paul Department of Neurology, Director of Translational Research, Cedars-Sinai Medical Center, Davis Research Building, D-2091, 110 N. George Burns Road, 90048, Los Angeles, CA, USA aut Drug-Like Property Profiling of Novel Neuroprotective Compounds to Treat Acute Ischemic Stroke: Guidelines to Develop Pleiotropic Molecules [Elektronische Daten] [Paul Lapchak] 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 four novel molecules to be developed as an AIS treatment. Springer Science+Business Media, LLC, 2012 Ames test nationallicence Flavonoid nationallicence Chalcone nationallicence Flavone nationallicence MDCK nationallicence Screening nationallicence Pleiotropic nationallicence ADME nationallicence Toxicity nationallicence AIS : acute ischemic stroke nationallicence CLogP : partition coefficient nationallicence MDCK : Madin Darby canine kidney (MDCK) cell assay nationallicence MW : molecular weight nationallicence tPA : tissue plasminogen activator nationallicence tPSA : polar surface area nationallicence SAR : structure activity relationship nationallicence Translational Stroke Research Springer-Verlag 4/3(2013-06-01), 328-342 1868-4483 4:3<328 2013 4 12975 https://doi.org/10.1007/s12975-012-0200-y text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s12975-012-0200-y text/html Onlinezugriff via DOI NATIONALLICENCE 100 1- Lapchak Paul Department of Neurology, Director of Translational Research, Cedars-Sinai Medical Center, Davis Research Building, D-2091, 110 N. George Burns Road, 90048, Los Angeles, CA, USA aut NATIONALLICENCE 773 0- Translational Stroke Research Springer-Verlag 4/3(2013-06-01), 328-342 1868-4483 4:3<328 2013 4 12975 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer