Structure-Activity Study of Bioisosteric Trifluoromethyl and Pentafluorosulfanyl Indole Inhibitors of the AAA ATPase p97.

Abstract

Exploratory SAR studies of a new phenyl indole chemotype for p97 inhibition revealed C-5 indole substituent effects in the ADPGlo assay that did not fully correlate with either electronic or steric factors. A focused series of methoxy-, trifluoromethoxy-, methyl-, trifluoromethyl-, pentafluorosulfanyl-, and nitro-analogues was found to exhibit IC50s from low nanomolar to double-digit micromolar. Surprisingly, we found that the trifluoromethoxy-analogue was biochemically a better match of the trifluoromethyl-substituted lead structure than a pentafluorosulfanyl-analogue. Moreover, in spite of their almost equivalent strongly electron-depleting effect on the indole core, pentafluorosulfanyl- and nitro-derivatives were found to exhibit a 430-fold difference in p97 inhibitory activities. Conversely, the electronically divergent C-5 methyl- and nitro-analogues both showed low nanomolar activities.

DOI: 10.1021/acsmedchemlett.5b00364

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@article{Alverez2015StructureActivitySO, title={Structure-Activity Study of Bioisosteric Trifluoromethyl and Pentafluorosulfanyl Indole Inhibitors of the AAA ATPase p97.}, author={Celeste N Alverez and Michelle Arkin and Stacie L. Bulfer and Raffaele Colombo and Marina Kovaliov and Matthew G Laporte and Chaemin Lim and Mary M S Liang and William J. Moore and R. Jeffrey Neitz and Yongzhao Yan and Zhizhou Yue and Donna M. Huryn and Peter Wipf}, journal={ACS medicinal chemistry letters}, year={2015}, volume={6 12}, pages={1225-30} }