Agrawal V K, Tang S B, Wolowyk M W, Knaus E E
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Drug Des Deliv. 1988 Dec;3(4):297-307.
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.
制备了2-氨基-3-硝基吡啶（4；结构见表I）和2-氨基-3-硝基-1H-吡啶-6-酮（5）的衍生物，它们被设想为组胺H2受体拮抗剂的环状“脲类似物”。使用组胺诱导的豚鼠心房变时反应进行的药理测试表明，R1-吡啶基取代基是活性的决定因素，因为在异构体系列中，4-吡啶基的相对活性大于3-吡啶基和2-吡啶基。与类似的2-氨基-3-硝基吡啶（4）相比，2-氨基-3-硝基-1H-吡啶-6-酮（5）的组胺H2受体拮抗剂活性显著较低。活性的降低归因于C-6氧代取代基的存在导致偶极取向改变，和/或氧代在降低亲脂性方面的总体作用。最有效的拮抗剂2-[(2-[(4-吡啶基)甲硫基]乙基氨基])-3-硝基-6-甲氧基吡啶的活性比西咪替丁低四倍。
