尾-Secretase (BACE1) Inhibitors with High in Vivo Efficacy Suitable for Clinical Evaluation in Alzheimer鈥檚 Disease
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- 作者：Hans Hilpert ; Wolfgang Guba ; Thomas J. Woltering ; Wolfgang Wostl ; Emmanuel Pinard ; Harald Mauser ; Alexander V. Mayweg ; Mark Rogers-Evans ; Roland Humm ; Daniela Krummenacher ; Thorsten Muser ; Christian Schnider ; Helmut Jacobsen ; Laurence Ozmen ; Alessandra Bergadano ; David W. Banner ; Remo Hochstrasser ; Andreas Kuglstatter ; Pascale David-Pierson ; Holger Fischer ; Alessandra Polara ; Robert Narquizian
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：May 23, 2013
- 年：2013
- 卷：56
- 期：10
- 页码：3980-3995
- 全文大小：735K
- 年卷期：v.56,no.10(May 23, 2013)
- ISSN：1520-4804
文摘
An extensive fluorine scan of 1,3-oxazines revealed the power of fluorine(s) to lower the pKa and thereby dramatically change the pharmacological profile of this class of BACE1 inhibitors. The CF3 substituted oxazine 89, a potent and highly brain penetrant BACE1 inhibitor, was able to reduce significantly CSF A尾40 and 42 in rats at oral doses as low as 1 mg/kg. The effect was long lasting, showing a significant reduction of A尾40 and 42 even after 24 h. In contrast to 89, compound 1b lacking the CF3 group was virtually inactive in vivo.