Peptidomimetic 尾-Secretase Inhibitors Comprising a Sequence of Amyloid-尾 Peptide for Alzheimer鈥檚 Disease

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• 作者：Helder Vila-Real ; Helena Coelho ; Jo茫o Rocha ; Adelaide Fernandes ; M. Rita Ventura ; Christopher D. Maycock ; Olga Iranzo ; Ana L. Simpl铆cio
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：July 23, 2015
• 年：2015
• 卷：58
• 期：14
• 页码：5408-5418
• 全文大小：655K
• ISSN：1520-4804

文摘

Alzheimer鈥檚 disease is a grave social problem in an aging population. A major problem is the passage of drugs through the blood鈥揵rain barrier. This work tests the hypothesis that the conjugation of peptidomimetic 尾-secretase inhibitors with a fragment of amyloid-尾 peptide facilitates entrance into the central nervous system. HVR-3 (compound 4), one of the conjugation products, was found to be as potent as OM00-3, a known peptidomimetic inhibitor, 4-fold more selective toward 尾-secretase 1 in relation to 尾-secretase 2 and 3-fold more resistant to in vitro metabolization in human serum. Its intravenous administration to mice and Wistar rats generated an active metabolite recovered from the rodent鈥檚 brains.