Bicyclic Inhibitors of Branched-Chain α-Keto Acid Dehydrogenase Kinase (BDK) with In Vivo Activity
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.
Authors
- Jue Liang (ORCID: https://orcid.org/0000-0002-9068-3292)
- Richard Wynn (ORCID: https://orcid.org/0000-0002-1879-2136)
- David Chuang (ORCID: https://orcid.org/0000-0002-3640-8927)
- Francisco Ortiz (ORCID: https://orcid.org/0000-0001-9357-0472)
- Joseph M. Ready (ORCID: https://orcid.org/0000-0003-1305-9581)
- Noelle Sevilir Williams (ORCID: https://orcid.org/0000-0003-1894-5742)
- Xiaoyu Wang (ORCID: https://orcid.org/0000-0002-0861-0204)
- Chen Gao (ORCID: https://orcid.org/0000-0001-7883-3270)
- Gauri Shishodia
- Tian Liu
Institutions
- Southwestern Medical Center (US)
- University of Cincinnati (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2024-10-28
- DOI
- https://doi.org/10.1021/acsmedchemlett.4c00362
- Citations
- 1
- Primary Topic
- Metabolomics and Mass Spectrometry Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.23
Funders
- U.S. Department of Defense
- Welch Foundation