Nakajima T, Nakajima S, Izawa T, Kashiwabara T, Munezuka Y
Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Gunma, Japan.
Chem Pharm Bull (Tokyo). 1994 Dec;42(12):2483-90. doi: 10.1248/cpb.42.2483.
A new series of cyanoamidines, N-arylalkyl-N'-cyano-3-pyridinecarboxamidines was synthesized and evaluated for inhibitory effects on 40 mM KCl-induced contraction and norepinephrine (NE)-induced contraction of rat aorta strips. The N-phenethyl cyanoamidine 4c showed potent vasodilatory action. Further in vitro screening program using 4c as a lead compound resulted in the discovery of highly potent N-[2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine (5j). Compound 5j induced the greatest increase in 86Rb+ efflux among cyanoamidine series. Subsequent modification of the pyridine ring of 5j was performed with evaluation for intravenous and oral antihypertensive activities. Introduction of an amino group at the 5-position of the pyridine ring furnished the new potassium channel opener, 5-amino-N-[2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine+ ++ (9e; KRN4884), which showed highly potent antihypertensive activity and a long duration of antihypertensive action after oral administration. KRN4884 is under further development as an antihypertensive agent.
合成了一系列新型氰基脒，即N-芳基烷基-N'-氰基-3-吡啶甲脒，并评估了它们对40 mM氯化钾诱导的大鼠主动脉条收缩以及去甲肾上腺素（NE）诱导的大鼠主动脉条收缩的抑制作用。N-苯乙基氰基脒4c表现出强效的血管舒张作用。以4c作为先导化合物进行进一步的体外筛选程序，发现了高效的N-[2-(2-氯苯基)乙基]-N'-氰基-3-吡啶甲脒（5j）。在氰基脒系列中，化合物5j引起的86Rb+外流增加最为显著。随后对5j的吡啶环进行修饰，并评估其静脉内和口服的抗高血压活性。在吡啶环的5位引入氨基得到了新型钾通道开放剂5-氨基-N-[2-(2-氯苯基)乙基]-N'-氰基-3-吡啶甲脒（9e；KRN4884），该化合物口服后表现出高效的抗高血压活性和持久的抗高血压作用。KRN4884作为一种抗高血压药物正在进一步研发中。
