Synthesis and SAR of a novel Kir6.2/SUR1 channel opener scaffold identified by HTS

Cayden J Dodd; Keagan S Chronister; Upendra Rathnayake; Lauren C Parr; Kangjun Li; Sichen Chang; Dehui Mi; Emily L Days; Joshua A Bauer; Hyekyung P Cho; Olivier Boutaud; Jerod S Denton; Craig W Lindsley; Changho Han

doi:10.1016/j.bmcl.2023.129256

Synthesis and SAR of a novel Kir6.2/SUR1 channel opener scaffold identified by HTS

Bioorg Med Chem Lett. 2023 May 1:87:129256. doi: 10.1016/j.bmcl.2023.129256. Epub 2023 Mar 24.

Authors

Affiliations

¹ Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
² Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
³ Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.
⁴ Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA; Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.
⁵ Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA; Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁶ Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: craig.lindsley@vanderbilt.edu.
⁷ Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: changho.han@vanderbilt.edu.

Abstract

Kir6.2/SUR1 is an ATP-regulated potassium channel that acts as an intracellular metabolic sensor, controlling insulin and appetite-stimulatory neuropeptides secretion. In this Letter, we present the SAR around a novel Kir6.2/SUR1 channel opener scaffold derived from an HTS screening campaign. New series of compounds with tractable SAR trends and favorable potencies are reported.

Keywords: Insulin homeostasis; Ion channel opener; K(ATP) channels; Kir6.2/SUR1; Structure-Activity Relationship (SAR).

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Sulfonylurea Receptors* / metabolism

Substances

Sulfonylurea Receptors

Abstract

Publication types

MeSH terms

Substances

Grants and funding