Targeting carnitine biosynthesis: discovery of new inhibitors against γ-butyrobetaine hydroxylase

J Med Chem. 2014 Mar 27;57(6):2213-36. doi: 10.1021/jm401603e. Epub 2014 Mar 14.


γ-Butyrobetaine hydroxylase (BBOX) catalyzes the conversion of gamma butyrobetaine (GBB) to l-carnitine, which is involved in the generation of metabolic energy from long-chain fatty acids. BBOX inhibitor 3-(1,1,1-trimethylhydrazin-1-ium-2-yl)propanoate (mildronate), which is an approved, clinically used cardioprotective drug, is a relatively poor BBOX inhibitor and requires high daily doses. In this paper we describe the design, synthesis, and properties of 51 compounds, which include both GBB and mildronate analogues. We have discovered novel BBOX inhibitors with improved IC50 values; the best examples are in the nanomolar range and about 2 orders of magnitude better when compared to mildronate. For six inhibitors, crystal structures in complex with BBOX have been solved to explain their activities and pave the way for further inhibitor design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calorimetry
  • Carnitine / antagonists & inhibitors*
  • Carnitine / biosynthesis*
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Indicators and Reagents
  • Kinetics
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Methylhydrazines / chemistry
  • Methylhydrazines / pharmacology
  • Models, Molecular
  • Molecular Conformation
  • Protein Binding
  • Recombinant Proteins / chemistry
  • Structure-Activity Relationship
  • gamma-Butyrobetaine Dioxygenase / antagonists & inhibitors*
  • gamma-Butyrobetaine Dioxygenase / genetics


  • Enzyme Inhibitors
  • Indicators and Reagents
  • Ligands
  • Methylhydrazines
  • Recombinant Proteins
  • 3-(2,2,2-trimethylhydrazine)propionate
  • gamma-Butyrobetaine Dioxygenase
  • Carnitine

Associated data

  • PDB/4BG1
  • PDB/4BGK
  • PDB/4BGM
  • PDB/4BHF
  • PDB/4BHI
  • PDB/4C5W