Brain-Penetrant Tetrahydronaphthalene Thromboxane A2-Prostanoid (TP) Receptor Antagonists as Prototype Therapeutics for Alzheimer’s Disease
| Autor: | Shimpei Sugiyama, John Q. Trojanowski, Xiaozhao Wang, Virginia M.-Y. Lee, Michael J. James, Katie Herbst-Robinson, Amos B. Smith, James H. Soper, Carlo Ballatore, Kurt R. Brunden |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
medicine.medical_specialty
Tetrahydronaphthalenes Physiology Thromboxane Cognitive Neuroscience BACE1-AS Enzyme-Linked Immunosorbent Assay Pharmacology Biochemistry Polymerase Chain Reaction Receptors Thromboxane A2 Prostaglandin H2 Thromboxane receptor Thromboxane A2 chemistry.chemical_compound Mice Alzheimer Disease Internal medicine medicine Amyloid precursor protein Animals Senile plaques Receptor Amyloid beta-Peptides biology Chemistry P3 peptide Cell Biology General Medicine Endocrinology Blood-Brain Barrier biology.protein Female |
| Popis: | A hallmark pathological feature of the Alzheimer's disease (AD) brain is the presence of senile plaques, which comprise amyloid β (Aβ) peptides that are derived from the amyloid precursor protein (APP). The plaque-containing AD brain is thought to be under oxidative stress, as evidenced by increased lipid oxidation products that include isoprostane-F2αIII (iPF2αIII). IPF2αIII can bind to and activate the thromboxane A2-prostanoid (TP) receptor, and TP receptor activation causes increased Aβ production through enhancement of APP mRNA stability. Moreover, TP receptor antagonists have been shown to block iPF2αIII-induced increases of Aβ secretion. Thus, the TP receptor may be a potential drug target for AD therapy. However, here we show that existing TP receptor antagonists have poor blood-brain barrier (BBB) permeability, likely due to the presence of a carboxylic acid moiety that is believed to be important for receptor interaction, but which may hamper passive diffusion across the BBB. We now report selected analogues of a known tetrahydronaphthalene TP receptor antagonist, wherein the carboxylic acid moiety has been replaced by heterocyclic bioisosteres. These heterocyclic analogues retained relatively high affinity for the mouse and human TP receptors, and, unlike the parent carboxylic acid compound, several examples freely diffused across the BBB into the brain upon administration to mice. These results reveal that brain-penetrant tetrahydronaphthalene TP receptor antagonists can be developed by substituting the carboxylic acid moiety with a suitable nonacidic bioisostere. Compounds of this type hold promise as potential lead structures to develop drug candidates for the treatment of AD. |
| Databáze: | OpenAIRE |
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