Back to your search result

Description

A cell-permeable chlorophenylpropionate compound that is superior to its structural analog 4PB (Cat. No. 567616) as an inhibitor against mitochondrial BCKDC (branched-chain alpha-ketoacid dehydrogenase complex) regulatory kinase BDK (BCKD kinase, IC50 = 6.3 vs. 53.1 µ,M) due to much optimized affinity toward the BDK N-terminal allosteric site (Kd = 2.4 vs. 5.7 µ,M) via carboxylate oxygens-mediated hydrogen bonds, as well as hydrophobic interactions mediated by the alpha-chlorine and the phenyl ring, effectively blocking BDK substrate access by preventing BDK interaction with the homo-24-meric dihydrolipoyltransferase BCKDC E2 component, while exhibiting little potency against PDK2 (pyruvate dehydrogenase kinase isoform 2) or BDP (BCKD phosphatase) even at concentrations as high as 1 mM (<10% inhibition). Shown to effectively reduce E1-alpha Ser293 phosphorylation with concomitant BCKDC activity upregulation in multiple tissues in mice (EDmax =160 mg/kg via i.p., 60 min) in vivo, resulting in significant downregulation of serum BCAA (branched-chain amino acid) Leu/Ile and Val levels. Pharmacokinetic studies reveal good stability in vitro (half-life = 3.1 h and 6.8 h using murine liver S9 preparation or murine hepatocytes, respectively) and low clearance in vivo (CL/F = 0.113 mL/min, 40 mg/kg i.p.), however the compound does not penetrate tissues efficiently (VZ/F = 20.8 mL, 40 mg/kg i.p.) and high dosages are recommended for mice treatment., A cell-permeable chlorophenylpropionate compound that is superior to its structural analog 4PB (Cat. No. 567616) as an inhibitor against mitochondrial branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) regulatory kinase BDK (BCKD kinase, IC50 = 6.3 vs. 53.1 M) due to much optimized affinity toward the BDK N-terminal allosteric site (Kd = 2.4 vs. 5.7 M), effectively blocking BDK substrate access by preventing BDK interaction with the homo-24-meric dihydrolipoyltransferase BCKDC E2 component, while exhibiting little potency against PDK2 or BCKD phosphatase BDP even at concentrations as high as 1 mM (<10% inhibition). Shown to effectively reduce E1-alpha Ser293 phosphorylation with concomitant BCKDC activity upregulation in multiple tissues in mice (EDmax =160 mg/kg via i.p.) in vivo. Despite good stability and low in vivo clearance , high doses are recommended for mice treatment due to low tissue penetration efficiency.