title: Inhibition of microsomal biotransformation by a series of nitrogen and oxygen heterocyclic histamine H2-antagonists.
abstract: A homologous series of potent, long-lasting thiazolo-pyrimidone-pyridine histamine H2-antagonists were examined for their inhibitory effects on rat hepatic ethylmorphine N-demethylation. Inhibitory potency increased in the order: 2-pyridinyl less than 3-pyridinyl less than 4-pyridinyl histamine H2-antagonist. Substitution ortho to the pyridine nitrogen decreased inhibitory potency. Hydroxylation of the pyridine heterocycle decreased inhibitory potency, whereas substituent electronic effects did not appreciably alter the inhibitory potency of these compounds. Antagonists containing oxygen heterocycles were moderately potent inhibitors compared to those containing unsubstituted pyridine as the heterocycle. A 3-(6-methylpyridine) histamine H2-antagonist was shown to be a slightly more potent inhibitor of ethinamate metabolism than cimetidine in rats. However, unlike cimetidine, it did not inhibit the plasma half-life of antipyrine in dogs at doses that were equally efficacious in inhibiting gastric acid secretion.
mesh_terms: D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D002927:Cimetidine / Q000494:pharmacology; D005037:Ethylmorphine-N-Demethylase / Q000037:antagonists & inhibitors*; D006571:Heterocyclic Compounds; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009584:Nitrogen; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors*; D010100:Oxygen; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
chemical_list: D006571:Heterocyclic Compounds; D006635:Histamine H2 Antagonists; D002927:Cimetidine; D010089:Oxidoreductases, N-Demethylating; D005037:Ethylmorphine-N-Demethylase; D009584:Nitrogen; D010100:Oxygen