Brain-Penetrant Tetrahydronaphthalene Thromboxane A2-Prostanoid (TP) Receptor Antagonists as Prototype Therapeutics for Alzheimer鈥檚 Disease
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- 作者：James H. Soper ; Shimpei Sugiyama ; Katie Herbst-Robinson ; Michael J. James ; Xiaozhao Wang ; John Q. Trojanowski ; Amos B. Smith ; III ; Virginia M.-Y. Lee ; Carlo Ballatore ; Kurt R. Brunden
- 刊名：ACS Chemical Neuroscience
- 出版年：2012
- 出版时间：November 21, 2012
- 年：2012
- 卷：3
- 期：11
- 页码：928-940
- 全文大小：571K
- 年卷期：v.3,no.11(November 21, 2012)
- ISSN：1948-7193
文摘
A hallmark pathological feature of the Alzheimer鈥檚 disease (AD) brain is the presence of senile plaques, which comprise amyloid 尾 (A尾) 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-F2伪III (iPF2伪III). IPF2伪III can bind to and activate the thromboxane A2-prostanoid (TP) receptor, and TP receptor activation causes increased A尾 production through enhancement of APP mRNA stability. Moreover, TP receptor antagonists have been shown to block iPF2伪III-induced increases of A尾 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selected analogues of a known tetrahydronaphthalene TP receptor antagonist, wherein the carboxylic acid moiety has been replaced by heterocyclic bioisosteres.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.