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

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 w...

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Bibliographic Details
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
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00365a020