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

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-10-28 eCollection Date: 2024-11-14 DOI:10.1021/acsmedchemlett.4c00362

Jue Liang, Xiaoyu Wang, Francisco Ortiz, Gauri Shishodia, Tian Liu, Chen Gao, Noelle S Williams, David T Chuang, R Max Wynn, Joseph M Ready

引用次数: 0

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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具有体内活性的支链α-酮酸脱氢酶激酶（BDK）双环抑制剂。

支链α-氨基酸缬氨酸、亮氨酸和异亮氨酸水平的升高与心脏病和代谢紊乱有关。激酶 BDK 又称支链酮酸脱氢酶激酶（BCKDK），它通过使支链 α-酮酸脱氢酶复合物 BCKDC 失活来负向调节支链 α-氨基酸的代谢。BDK 抑制剂可提高 BCKDC 的活性，从而成为治疗心脏代谢疾病的有用药物。我们介绍了一种新型双环羧酰胺，它是一种具有体内活性的 BDK 抑制剂。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.

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