Gordon, Christopher P., Venn-Brown, Barbara, Robertson, Mark J., Young, Kelly A., Chau, Ngoc, Mariana, Anna, Whiting, Ainslie, Chircop, Megan, Robinson, Phillip J., and McCluskey, Adam (2013) Development of second-generation indole-based dynamin GTPase inhibitors. Journal of Medicinal Chemistry, 56 (1). pp. 46-59.

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Abstract

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, IC50(dyn I) = 7.7 µM), reduced under flow chemistry conditions (20, IC50(dyn I) = 5.2 µM) 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 (IC50 (dyn I) = 0.56 µM) and 25 (IC50(dyn I) = 0.76 µM), stood out. Indole 24 is nontoxic and showed increased potency against dynamin I and II in vitro and in cells (IC50(CME) = 1.9 µM). 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.

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