Development of Second-Generation Indole-Based Dynamin GTPase Inhibitors

• Published in: Journal of medicinal chemistry 2013-01, Vol.56 (1), p.46-59
• Main Authors: Gordon, Christopher P, Venn-Brown, Barbara, Robertson, Mark J, Young, Kelly A, Chau, Ngoc, Mariana, Anna, Whiting, Ainslie, Chircop, Megan, Robinson, Phillip J, McCluskey, Adam
• Format: Article
• Language: English
• Subjects: Acrylamides - chemical synthesis; Acrylamides - chemistry; Acrylamides - pharmacology; Animals; Brain - enzymology; Cell Line, Tumor; Dynamin I - antagonists & inhibitors; Dynamin I - chemistry; Dynamin II - antagonists & inhibitors; Dynamin II - chemistry; Endocytosis; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Sheep; Small Molecule Libraries; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm300844m

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.