Development of Second-Generation Indole-Based Dynamin GTPase Inhibitors

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• 作者：Christopher P. Gordon ; Barbara Venn-Brown ; Mark J. Robertson ; Kelly A. Young ; Ngoc Chau ; Anna Mariana ; Ainslie Whiting ; Megan Chircop ; Phillip J. Robinson ; Adam McCluskey
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：January 10, 2013
• 年：2013
• 卷：56
• 期：1
• 页码：46-59
• 全文大小：463K
• 年卷期：v.56,no.1(January 10, 2013)
• ISSN：1520-4804

文摘

Focused library development of our lead 2-cyano-3-(1-(3-(dimethylamino)propyl)-2-methyl-1H-indol-3-yl)-N-octylacrylamide (2) confirmed the tertiary dimethylamino-propyl moiety as critical for inhibition of dynamin GTPase. The cyanoamide moiety could be replaced with a thiazole-4(5H)-one isostere (19, IC_50(dyn聽I) = 7.7 渭M), reduced under flow chemistry conditions (20, IC_50(dyn聽I) = 5.2 渭M) or replaced by a simple amine. The latter provided a basis for a high yield library of compounds via a reductive amination by flow hydrogenation. Two compounds, 24 (IC_{50聽(dyn聽I)} = 0.56 渭M) and 25 (IC_50(dyn聽I) = 0.76 渭M), stood out. Indole 24 is nontoxic and showed increased potency against dynamin I and II in vitro and in cells (IC_50(CME) = 1.9 渭M). It also showed 4.4-fold selectivity for dynamin I. The indole 24 compound has improved isoform selectivity and is the most active in-cell inhibitor of clathrin-mediated endocytosis reported to date.