Inhibitors of indoleethylamine N-methyltransferase. Derivatives of 3-methyl-2-thiazolidinimine. In vitro, in vivo, and metabolic studies

J Med Chem. 1980 Jul;23(7):773-80. doi: 10.1021/jm00181a014.

Abstract

A variety of substituent groups has been attached to the exocyclic imine function of 2-imino-3-methylthiazolidine (1) in a search for metabolic precursors of this potent inhibitor of the enzyme indoleethylamine N-methyltransferase (INMT) which would exhibit superior pharmacodynamic properties in animals. It has been determined that chemically stable derivatives of 1 based on succinic, nicotinic, and N-acylated amino acids, although they lack in vitro efficacy, are potent inhibitors of INMT when administered orally or intravenously to rabbits. Metabolic studies carried out with 14C-labeled N,N'-bix(3-methyl-2-thiazolidinylidene)succinamide (3) have established that conversion of this compound to 1 occurs both in the whole rabbit and in the isolated rabbit liver. 1 itself has been shown to be metabolically inert in rabbits, being excreted primarily in the urine.

MeSH terms

  • Administration, Oral
  • Animals
  • Biotransformation
  • Humans
  • Imines / chemical synthesis*
  • Imines / metabolism
  • Imines / pharmacology
  • In Vitro Techniques
  • Injections, Intravenous
  • Liver / metabolism
  • Lung / enzymology
  • Male
  • Methyltransferases / antagonists & inhibitors*
  • Rabbits
  • Thiazoles / chemical synthesis*
  • Thiazoles / metabolism
  • Thiazoles / pharmacology
  • Tissue Distribution
  • Tryptamines / antagonists & inhibitors

Substances

  • Imines
  • Thiazoles
  • Tryptamines
  • Methyltransferases
  • indoleethylamine N-methyltransferase