Bicyclic\nInhibitors of Branched-Chain α‑Keto\nAcid Dehydrogenase Kinase (BDK) with In Vivo Activity

Elevated levels of the branched chain α-amino acids\nvaline,\nleucine, and isoleucine are associated with heart disease and metabolic\ndisorders. The kinase BDK, also known as branched-chain ketoacid dehydrogenase\nkinase (BCKDK), is a negative regulator of branched-chain α-amino\nacid metabolism through deactivation of BCKDC, the branched-chain\nα-ketoacid dehydrogenase complex. Inhibitors of BDK increase\nthe activity of BCKDC and could be useful therapeutic leads for cardiometabolic\ndiseases. We describe a novel bicyclic carboxy amide as an inhibitor\nof BDK with in vivo activity.