| Autor: |
Bertron JL; Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States., Duvernay MT; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States., Mitchell SG; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States., Smith ST; Chemical and Physical Biology Program, Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37232, United States., Maeng JG; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States., Blobaum AL; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States., Davis DC; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States., Meiler J; Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.; Institute for Drug Discovery, Leipzig University, Saxony 04109, Germany., Hamm HE; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States., Lindsley CW; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States. |
| Abstrakt: |
The detailed pharmacology and therapeutic potential of the central PAR4 receptors are poorly understood due to a lack of potent, selective, and brain-penetrant tool compounds. Despite this, robust data with biochemical and genetic tools show the therapeutic potential of PAR4 antagonists in traumatic brain injury, Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders with a neuroinflammatory component. Thus, we performed a functional HTS campaign, identified a fundamentally new PAR4 competitive inhibitor chemotype, optimized this new series (increased potency >45-fold), discovered enantiospecific activity (though opposing preference for human versus mouse PAR4), and engendered high central nervous system penetration (rat K p 's of 0.52 to 4.2 and K p,uu 's of 0.52 to 1.2). |
