Structure–activity relationship studies in a new series of 2-amino-N-phenylacetamide inhibitors of Slack potassium channels

Alshaima'a M. Qunies, Nigam M. Mishra, Brittany D. Spitznagel, Yu Du, Valerie S. Acuña, C. David Weaver, Kyle A. Emmitte

Research output: Contribution to journalArticlepeer-review

Abstract

In this Letter we describe structure–activity relationship (SAR) studies conducted in five distinct regions of a new 2-amino-N-phenylacetamides series of Slack potassium channel inhibitors exemplified by recently disclosed high-throughput screening (HTS) hit VU0606170 (4). New analogs were screened in a thallium (Tl+) flux assay in HEK-293 cells stably expressing wild-type human (WT) Slack. Selected analogs were screened in Tl+ flux versus A934T Slack and other Slo family members Slick and Maxi-K and evaluated in whole-cell electrophysiology (EP) assays using an automated patch clamp system. Results revealed the series to have flat SAR with significant structural modifications resulting in a loss of Slack activity. More minor changes led to compounds with Slack activity and Slo family selectivity similar to the HTS hit.

Original languageEnglish
Article number129013
JournalBioorganic and Medicinal Chemistry Letters
Volume76
DOIs
StatePublished - 15 Nov 2022

Keywords

  • 2-Amino-N-phenylacetamide
  • EIMFS
  • K1.1
  • KCNT1
  • MMPSI
  • Slack
  • Slo2.2

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