Discovery of N-(4-Aminobutyl)- N'-(2-methoxyethyl)guanidine as the First Selective, Nonamino Acid, Catalytic Site Inhibitor of Human Dimethylarginine Dimethylaminohydrolase-1 (h DDAH-1)

J Med Chem. 2020 Jan 9;63(1):425-432. doi: 10.1021/acs.jmedchem.9b01230. Epub 2019 Dec 31.

Abstract

N-(4-Aminobutyl)-N'-(2-methoxyethyl)guanidine (8a) is a potent inhibitor targeting the hDDAH-1 active site (Ki = 18 μM) and derived from a series of guanidine- and amidine-based inhibitors. Its nonamino acid nature leads to high selectivities toward other enzymes of the nitric oxide-modulating system. Crystallographic data of 8a-bound hDDAH-1 illuminated a unique binding mode. Together with its developed N-hydroxyguanidine prodrug 11, 8a will serve as a most widely applicable, pharmacological tool to target DDAH-1-associated diseases.

MeSH terms

  • Amidohydrolases / antagonists & inhibitors*
  • Amidohydrolases / chemistry
  • Amidohydrolases / metabolism
  • Catalytic Domain / drug effects
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Guanidines / chemical synthesis
  • Guanidines / chemistry*
  • Guanidines / metabolism
  • Humans
  • Protein Binding

Substances

  • Enzyme Inhibitors
  • Guanidines
  • Amidohydrolases
  • dimethylargininase