Bicyclic Inhibitors of Branched-Chain α-Keto Acid Dehydrogenase Kinase (BDK) with In Vivo Activity

  • ACS Med Chem Lett. 2024 Oct 28;15(11):1899-1906. doi: 10.1021/acsmedchemlett.4c00362.
Jue Liang  1 ,  Xiaoyu Wang  1 ,  Francisco Ortiz  1 ,  Gauri Shishodia  1 ,  Tian Liu  2 ,  Chen Gao  2 ,  Noelle S Williams  1 ,  David T Chuang  1 ,  R Max Wynn  1 ,  Joseph M Ready  1
Affiliations
  • 1. Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas 75390-9038, United States.
  • 2. Department of Pharmacology and Systems Physiology, University of Cincinnati, 3230 Eden Avenue, Cincinnati, Ohio 45267, United States.
PMID: 39563832 DOI: 10.1021/acsmedchemlett.4c00362
Abstract

Elevated levels of the branched chain α-amino acids valine, leucine, and isoleucine are associated with Heart Disease and metabolic disorders. The kinase BDK, also known as branched-chain ketoacid dehydrogenase kinase (BCKDK), is a negative regulator of branched-chain α-amino acid metabolism through deactivation of BCKDC, the branched-chain α-ketoacid dehydrogenase complex. Inhibitors of BDK increase the activity of BCKDC and could be useful therapeutic leads for cardiometabolic diseases. We describe a novel bicyclic carboxy amide as an inhibitor of BDK with in vivo activity.

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