Drug-Like Property Profiling of Novel Neuroprotective Compounds to Treat Acute Ischemic Stroke: Guidelines to Develop Pl
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ORIGINAL ARTICLE
Drug-Like Property Profiling of Novel Neuroprotective Compounds to Treat Acute Ischemic Stroke: Guidelines to Develop Pleiotropic Molecules Paul A. Lapchak
Received: 13 April 2012 / Revised: 24 May 2012 / Accepted: 12 July 2012 / Published online: 14 August 2012 # Springer Science+Business Media, LLC 2012
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 derisking 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).
P. A. Lapchak (*) Department of Neurology, Director of Translational Research, Cedars-Sinai Medical Center, Davis Research Building, D-2091, 110 N. George Burns Road, Los Angeles, CA 90048, USA e-mail: [email protected]
Using this series of assays, we have identified four novel molecules to be developed as an AIS treatment. Keywords Ames test . Flavonoid . Chalcone . Flavone . MDCK . Screening . Pleiotropic . ADME . Toxicity Abbreviations AIS acute ischemic stroke CLogP partition coefficient MDCK Madin Darby canine kidney (MDCK) cell assay MW molecular weight tPA tissue plasminogen activator tPSA polar surface area SAR structure activity relationship
Introduction There is substantial risk associated with drug development for acute ischemic stroke (AIS), but the benefit to patients associated with a Food and Drug Administration (FDA) approved neuroprotective therapy is enormous [5]. Currently, tissue plasminogen activator (tPA) is the only FDA approved treatment for AIS based upon the original National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study [6]. Ev
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