title: Synthesis and activity of pyridine analogues of histamine H2-receptor antagonists.
abstract: Derivatives of 2-amino-3-nitropyridine (4; see Table I for structures) and 2-amino-3-nitro-1H-pyrid-6-one (5), conceived as cyclic 'urea equivalents' of histamine H2-receptor antagonists, were prepared. Pharmacological testing, using the histamine-induced guinea pig atrial chronotropic response, indicated that the R1-pyridyl substituent was a determinant of activity, since the relative activities within an isomeric series were 4-pyridyl greater than 3- and 2-pyridyl. In comparison with analogous 2-amino-3-nitropyridines. (4), 2-amino-3-nitro-1H-pyrid-6-ones (5) had a substantially less histamine H2-receptor antagonist activity. This reduction in activity is attributed to altered orientation of the dipole due to the presence of the C-6 oxo substituent, and/or to the overall effect of oxo in decreasing lipophilicity. The most potent antagonist, 2-[( 2-[(4-pyridyl)methylthio]ethylamino])-3-nitro-6-methoxypyridine, was four times less active than cimetidine.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
authors.forename: V K
authors.initials: VK
authors.lastname: Agrawal
authors.forename: S B
authors.initials: SB
authors.lastname: Tang
authors.forename: M W
authors.initials: MW
authors.lastname: Wolowyk
authors.forename: E E
authors.initials: EE
authors.lastname: Knaus
mesh_terms: D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006635:Histamine H2 Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D006635:Histamine H2 Antagonists; D011725:Pyridines