Synthesis and activity of pyridine analogues of histamine H2-receptor antagonists

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.