A deuterium isotope effect on the inhibition of gastric secretion by N,N-dimethyl-N'-[2-(diisopropylamino)ethyl]-N'-(4,6-dimethyl-2-pyridyl)urea. Synthesis of metabolites

• Published in: Journal of medicinal chemistry 1983-11, Vol.26 (11), p.1650-1653
• Main Authors: Hoffman, Jacob M, Habecker, Charles N, Pietruszkiewicz, Adolph M, Bolhofer, William A, Cragoe, Edward J, Torchiana, Mary Lou, Hirschmann, Ralph
• Format: Article
• Language: English
• Subjects: Animals; Biotransformation; Chemistry; Deuterium; Dogs; Exact sciences and technology; Gastric Juice - drug effects; Gastric Juice - metabolism; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Magnetic Resonance Spectroscopy; Methylurea Compounds - chemical synthesis; Methylurea Compounds - metabolism; Methylurea Compounds - pharmacology; Organic chemistry; Preparations and properties; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00365a020

The use of isotopic substitution to retard the oxidative metabolism of the gastric antisecretory agent N,N-dimethyl-N'-[2-(diisopropylamino)ethyl]-N'-(4,6-dimethyl-2-pyridyl)urea (1) and improve its antisecretory potency was examined. The pyridine ring methyl hydrogens of 1 were replaced with either deuterium or fluorine. The hexadeuterated analogue (12) was found to be approximately 2.1 times more potent than the protio form (1) as an inhibitor of gastric acid secretion stimulated by gastrin tetrapeptide. The hexafluoro analogue (11) was 0.4 times as potent as 1. A useful pyridine ring synthesis was developed to prepare the metabolites of 1, 10a (4-hydroxymethyl) and 10b (6-hydroxymethyl), and the hexafluoro analogue 11. These syntheses involved the condensation of 1,3-diketones with an appropriately N-substituted amidinoacetate.