Discovery of S-adenosyl-L-homocysteine hydrolase inhibitors based on non-adenosine analogs

Bioorg Med Chem Lett. 2014 Sep 1;24(17):4336-40. doi: 10.1016/j.bmcl.2014.06.008. Epub 2014 Jun 21.

Abstract

High throughput screening using Automated Ligand Identification System (ALIS) resulted in the discovery of a new series of S-adenosyl-L-homocysteine hydrolase inhibitors based on non-adenosine analogs. The optimization campaign led to very potent and competitive compound 39 with a Ki value of 1.5 nM. Compound 39 could be a promising lead compound for research to reduce elevated homocysteine levels.

Keywords: Competitive; Homocysteine; S-Adenosyl-l-homocysteine hydrolase inhibitors.

MeSH terms

  • Adenosine / chemistry
  • Adenosylhomocysteinase / antagonists & inhibitors*
  • Adenosylhomocysteinase / metabolism
  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Amines / chemical synthesis
  • Amines / chemistry
  • Amines / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • High-Throughput Screening Assays
  • Humans
  • Molecular Structure
  • Monomethylhydrazine / chemical synthesis
  • Monomethylhydrazine / chemistry
  • Monomethylhydrazine / pharmacology*
  • Structure-Activity Relationship

Substances

  • Amides
  • Amines
  • Enzyme Inhibitors
  • Adenosylhomocysteinase
  • Adenosine
  • Monomethylhydrazine