具有体内活性的支链α-酮酸脱氢酶激酶（BDK）的双环抑制剂
Bicyclic Inhibitors of Branched-Chain α-Keto Acid Dehydrogenase Kinase (BDK) with In Vivo Activity.
作者信息
Liang Jue, Wang Xiaoyu, Ortiz Francisco, Shishodia Gauri, Liu Tian, Gao Chen, Williams Noelle S, Chuang David T, Wynn R Max, Ready Joseph M
机构信息
Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas 75390-9038, United States.
Department of Pharmacology and Systems Physiology, University of Cincinnati, 3230 Eden Avenue, Cincinnati, Ohio 45267, United States.
出版信息
ACS Med Chem Lett. 2024 Oct 28;15(11):1899-1906. doi: 10.1021/acsmedchemlett.4c00362. eCollection 2024 Nov 14.
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.
支链α-氨基酸缬氨酸、亮氨酸和异亮氨酸水平升高与心脏病和代谢紊乱有关。激酶BDK，也称为支链酮酸脱氢酶激酶（BCKDK），是通过使支链α-酮酸脱氢酶复合物BCKDC失活来调节支链α-氨基酸代谢的负调控因子。BDK抑制剂可增加BCKDC的活性，可能成为治疗心脏代谢疾病的有效先导药物。我们描述了一种新型双环羧酰胺作为具有体内活性的BDK抑制剂。
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