Acute ischemic stroke resulting from an embolism is now a treatable condition, because thrombolysis with tissue plasminogen activator (tPA) has been approved by the FDA. However, the utilization of tPA is limited by its short therapeutic window and increased risk of intracerebral hemorrhage. Because there is a need for safe and effective stroke treatments, we have concentrated on synthesizing, identifying, and developing novel classes of neuroprotective drugs. We have extensive preliminary evidence from in vitro and in vivo stroke models suggesting that the phenylpropanoid or polyphenol family of compounds, which includes (1) Chlorogenic acid; (2) Fisetin; and (3) Baicalein, may be useful to treat stroke. For this translational drug development program, we will use a screening funnel consisting of a combination of in vitro and in vivo stroke models to effectively develop new clinical candidates belonging to the family of compounds described above. First, we will create a focused diversity library that covers many possible substitution positions on the parent backbone (scaffold) of chlorogenic acid, fisetin and baicalein. The new molecules will be screened using two in vitro stroke assays to allow us to select the best and most 'active' compounds to be tested in vivo using the rabbit small clot embolism model (RSCEM), the stroke model used in the development of tPA. We will screen the compounds in vivo to select candidates that significantly improve clinical rating scores with long therapeutic windows. Once we have identified candidates, we will assess the pharmacokinetic and toxicity profiles of the compounds, and will also study the effects of administration of the novel neuroprotective agents in combination with tPA to select a patient population and determine if the compounds may have beneficial effects in combination with tPA. When the final candidate is selected, the drug will be synthesized for a clinical trial using a GMP-approved facility, an IND will be filed and a clinical trial will be initiated. Overall, we will identify a new neuroprotective compound that readily crosses the blood brain barrier, improves clinical rating scores following embolic strokes in rabbits and has a clean safety profile so that the neuroprotective compound can be developed to treat stroke.

Public Health Relevance

We will use a screening funnel consisting of in vitro and in vivo stroke models to effectively identify, optimize and develop new clinical candidates. The new neuroprotective compound that readily crosses the BBB and improves clinical rating scores with a long therapeutic window following embolic strokes in rabbits will further be developed to treat stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01NS060685-05
Application #
8500473
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Mcgavern, Linda
Project Start
2009-09-01
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Lapchak, Paul A; Boitano, Paul D (2014) Effect of the Pleiotropic Drug CNB-001 on Tissue Plasminogen Activator (tPA) Protease Activity in vitro: Support for Combination Therapy to Treat Acute Ischemic Stroke. J Neurol Neurophysiol 5:
Lapchak, Paul A; Lara, Jacqueline A; Boitano, Paul D (2014) 4-((1E)-2-(5-(4-hydroxy-3-methoxystyryl-)-1-phenyl-1H-pyrazoyl-3-yl) vinyl)-2-methoxy-phenol) (CNB-001) Does Not Regulate Human Recombinant Protein-Tyrosine Phosphatase1B (PTP1B) Activity in vitro. J Neurol Neurophysiol 5:
Panzhinskiy, Evgeniy; Hua, Yinan; Lapchak, Paul A et al. (2014) Novel curcumin derivative CNB-001 mitigates obesity-associated insulin resistance. J Pharmacol Exp Ther 349:248-57
Lapchak, Paul A (2013) Drug-like property profiling of novel neuroprotective compounds to treat acute ischemic stroke: guidelines to develop pleiotropic molecules. Transl Stroke Res 4:328-42
Lapchak, Paul A; Kikuchi, Kiyoshi; Butte, Pramod et al. (2013) Development of transcranial sonothrombolysis as an alternative stroke therapy: incremental scientific advances toward overcoming substantial barriers. Expert Rev Med Devices 10:201-13
Lapchak, Paul A (2013) Recommendations and practices to optimize stroke therapy: developing effective translational research programs. Stroke 44:841-3
Lapchak, Paul A (2013) Fast neuroprotection (fast-NPRX) for acute ischemic stroke victims: the time for treatment is now. Transl Stroke Res 4:704-9
Lapchak, Paul A; Doyan, Sarina; Fan, Xiaomin et al. (2013) Synergistic Effect of AJW200, a von Willebrand Factor Neutralizing Antibody with Low Dose (0.9 mg/mg) Thrombolytic Therapy Following Embolic Stroke in Rabbits. J Neurol Neurophysiol 4:
Lapchak, Paul A; Zhang, John H; Noble-Haeusslein, Linda J (2013) RIGOR guidelines: escalating STAIR and STEPS for effective translational research. Transl Stroke Res 4:279-85
Chiruta, Chandramouli; Schubert, David; Dargusch, Richard et al. (2012) Chemical modification of the multitarget neuroprotective compound fisetin. J Med Chem 55:378-89

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