Design and Synthesis of Mercaptoacetamides as Potent, Selective, and Brain Permeable Histone Deacetylase 6 Inhibitors

ACS Medicinal Chemistry Letters
Wei LvAlan P Kozikowski

Abstract

A series of nonhydroxamate HDAC6 inhibitors were prepared in our effort to develop potent and selective compounds for possible use in central nervous system (CNS) disorders, thus obviating the genotoxicity often associated with the hydroxamates. Halogens are incorporated in the cap groups of the designed mercaptoacetamides in order to increase brain accessibility. The indole analogue 7e and quinoline analogue 13a displayed potent HDAC6 inhibitory activity (IC50, 11 and 2.8 nM) and excellent selectivity against HDAC1. Both 7e and 13a together with their ester prodrug 14 and disulfide prodrugs 15 and 16 were found to be effective in promoting tubulin acetylation in HEK cells. The disulfide prodrugs 15 and 16 also released a stable concentration of 7e and 13a upon microsomal incubation. Administration of 15 and 16in vivo was found to trigger an increase of tubulin acetylation in mouse cortex. These results suggest that further exploration of these compounds for the treatment of CNS disorders is warranted.

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Citations

Feb 13, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Olga BakulinaMikhail Krasavin
Dec 24, 2019·Expert Opinion on Therapeutic Patents·Sida Shen, Alan P Kozikowski
Oct 10, 2020·European Journal of Medicinal Chemistry·Maurício T TavaresSida Shen
Nov 11, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Sravani PulyaBalaram Ghosh
Apr 4, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Dominika GyuranováMartin Rebroš
Jan 8, 2019·ACS Medicinal Chemistry Letters·Nicholas J PorterDavid W Christianson

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