Sircar I, Haleen S J, Burke S E, Barth H
Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
J Med Chem. 1992 Nov 13;35(23):4442-9. doi: 10.1021/jm00101a022.
A series of 4-(diphenylmethyl)-alpha-[(4-quinolinyloxy)methyl]-1-pipe razineethanol and closely related compounds was synthesized and evaluated for cardiac and vascular activity in isolated perfused rat and guinea pig hearts. Compound 1 produced greater inotropic effects in rat hearts than in guinea pig hearts, a phenomenon which was also observed with the prototype agent DPI 201-106. Compound 15 produced an inotropic effect with one-tenth the potency of compound 1. Both compounds 1 and 15 demonstrated direct inotropic and vasodilatory effects when administered iv in anesthetized dogs, although the vasodilatory activity was more pronounced with compound 15 than 1 and DPI compound. Compound 1 lacks the CN moiety which is a key structural requirement in DPI for positive inotropic activity. The synthesis, in vitro, and in vivo evaluations of these agents, and comparative data with DPI-201-106 (compound 17) are reported.
合成了一系列4-（二苯甲基）-α-[(4-喹啉氧基)甲基]-1-哌嗪乙醇及其密切相关的化合物，并在离体灌注的大鼠和豚鼠心脏中对其心脏和血管活性进行了评估。化合物1在大鼠心脏中产生的正性肌力作用比在豚鼠心脏中更强，原型药物DPI 201-106也观察到了这种现象。化合物15产生的正性肌力作用的效力是化合物1的十分之一。化合物1和15静脉注射给予麻醉犬时均表现出直接的正性肌力和血管舒张作用，尽管化合物15的血管舒张活性比化合物1和DPI化合物更明显。化合物1缺乏在DPI中对正性肌力活性起关键结构作用的-CN部分。报告了这些药物的合成、体外和体内评估以及与DPI-201-106（化合物17）的比较数据。
