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.

Absence of genotoxic effects of the chalcone (E)-1-(2-hydroxyphenyl)-3-(4-methylphenyl)-prop-2-en-1-one) and its potential chemoprevention against DNA damage using in vitro and in vivo assays

“…Several studies have reported the lack of mutagenic action for many classes of chalconas [ 38 , 39 ]. Furthemore, in a study using diferent hydroxychalcones, 4’5’-dimethyl-2’,3,4-trihydroxylchalcone, 6 methyl-2’,3,4-trihydroxychalcone, and 3,3’,4’,7-tetrahydroxyflavone, none of them presented mutagenic effect by the Ames test [ 40 ]. Also in our study, all the doses of 2HMC exhibited MI lower than the negative control (MI = 1.00) in both tester strains, indicating a possible toxic effect of this chalcone in S .…”

Cannabinoid receptor type 2 agonist attenuates apoptosis by activation of phosphorylated CREB–Bcl-2 pathway after subarachnoid hemorrhage in rats

“…However, quantification of TUNEL positive neurons would have certainly strengthened our hypothesis. Further studies are necessary for clinical translation (Bahjat et al, 2013; Lapchak, 2013; Tajiri et al, 2013). …”

The High Cost of Stroke and Stroke Cytoprotection Research

“…The development of a CNS-active drug to treat stroke requires special attention since they must be able to cross the blood-brain barrier (BBB) to penetrate into the penumbra. This can be taken into consideration when developing molecules using the Lipinski rules as well as utilizing BBB penetration assays (in vitro) for primary candidate selection and then in vivo for drug development [82–84]. Moreover, during the initial stages of drug development, rapid and cost-effective toxicity screens (CeeTox and micronucleus assays) can help eliminate compounds with excessive unwanted “side effects”.…”