Merck, 5056020001, BDK Inhibitor II, (S)-CPP

General 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 α-ketoacid dehydrogenase complex) regulatory kinase BDK (BCKD kinase; IC₅₀ = 6.3 vs. 53.1 µM) due to much optimized affinity toward the BDK N-terminal allosteric site (Kd = 2.4 vs. 5.7 µM) via carboxylate oxygens-mediated hydrogen bonds, as well as hydrophobic interactions mediated by the α-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 (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.
Biochem/physiol Actions
Primary Target
BDK
Reversible: yes
Cell permeable: yes
Packaging
Packaged under inert gas
Preparation Note
Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 1 month at -20°C.
Use only fresh DMSO for reconstitution.
Other Notes
Tso, S.C., et al. 2013. Proc. Natl. Acad. Sci. USA110, 9728.
Legal Information
CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany
Disclaimer
Toxicity: Standard Handling (A)