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

Autor: Qunies AM; Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA; Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX, USA., Mishra NM; Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA., Spitznagel BD; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA., Du Y; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA., Acuña VS; Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA., David Weaver C; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA., Emmitte KA; Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA. Electronic address: kyle.emmitte@unthsc.edu.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2022 Nov 15; Vol. 76, pp. 129013. Date of Electronic Publication: 2022 Sep 29.
DOI: 10.1016/j.bmcl.2022.129013
Abstrakt: 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.
Competing Interests: Declaration of Competing Interest Dr. C. David Weaver is an owner of WaveFront Biosciences and ION biosciences, makers of the Panoptic plate reader and Thallos, Tl(+)-sensitive fluorescent indicators used in the these studies, respectively.
(Copyright © 2022 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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