2. Academic Validation
  3. Development of second-generation indole-based dynamin GTPase inhibitors

Development of second-generation indole-based dynamin GTPase inhibitors

  • J Med Chem. 2013 Jan 10;56(1):46-59. doi: 10.1021/jm300844m.
Christopher P Gordon 1,  Barbara Venn-Brown,  Mark J Robertson,  Kelly A Young,  Ngoc Chau,  Anna Mariana,  Ainslie Whiting,  Megan Chircop,  Phillip J Robinson,  Adam McCluskey
Affiliations

Affiliation

  • 1 Chemistry, Centre for Chemical Biology, School of Environmental and Life Sciences, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
PMID: 23167654 DOI: 10.1021/jm300844m
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, IC(₅₀(dyn I)) = 7.7 μM), reduced under flow chemistry conditions (20, IC(₅₀(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 (IC(₅₀ (dyn I)) = 0.56 μM) and 25 (IC(₅₀(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 (IC(₅₀(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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