Discovery of 2-methylpyridine-based biaryl amides as 纬-secretase modulators for the treatment of Alzheimer鈥檚 disease
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- 作者：Jian Jeffrey Chen ; Wenyuan Qian ; Kaustav Biswas ; Chester Yuan ; Albert Amegadzie ; Qingyian Liu ; Thomas Nixey ; Joe Zhu ; Mqhele Ncube ; Robert M. Rzasa ; Frank Chavez Jr. ; Ning Chen ; Frenel DeMorin ; Shannon Rumfelt ; Christopher M. Tegley ; Jennifer R. Allen ; Stephen Hitchcock ; R ; y Hungate ; Michael D. Bartberger ; Leeanne Zalameda ; et al.
- 关键词：纬-Secretase modulator (GSM) ; 纬-Secretase inhibitor (GSI) ; Alzheimer&rsquo ; s disease (AD) ; Amyloid 尾-protein (A尾) ; Methylpyridine ; Amide as sulfonamide replacement
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：1 December, 2013
- 年：2013
- 卷：23
- 期：23
- 页码：6447-6454
- 全文大小：4912 K
文摘
纬-Secretase modulators (GSMs) are potentially disease-modifying treatments for Alzheimer鈥檚 disease. They selectively lower pathogenic A尾42 levels by shifting the enzyme cleavage sites without inhibiting 纬-secretase activity, possibly avoiding known adverse effects observed with complete inhibition of the enzyme complex. A cell-based HTS effort identified the sulfonamide 1 as a GSM lead. Lead optimization studies identified compound 25 with improved cell potency, PKDM properties, and it lowered A尾42 levels in the cerebrospinal fluid (CSF) of Sprague-Dawley rats following oral administration. Further optimization of 25 to improve cellular potency is described.