Can We Do Better Than Dobutamine?

The development of dobutamine, an infusible inotropic drug for heart failure, was first described in 1975. Although this sympathomimetic was designed to increase cardiac output, it is far from ideal as a long-term safe strategy. New drugs for acute heart failure are needed, and the successful development of new approaches will require diverse expertise and resources. In 1975, Tuttle and Mills1 published in Circulation Research an article entitled “Dobutamine: development of a new catecholamine to selectively increase cardiac contractility.” This work, having been cited >600 times, ranks 54th on the list of most cited articles from Circulation Research . Working at the Lilly Research Laboratories, a part of Eli Lilly, Tuttle, a pharmacologist, and Mills, a medicinal chemist, systematically modified the structure of isoproterenol/isoprenaline with the goal of generating new drugs to improve cardiac function. It was known that isoproterenol, through its action on β adrenergic receptors, could increase cardiac contractility but did so at the cost of increased heart rate and a concomitant proarrhythmic effect. Moreover, the increase in blood pressure that occurs with isoproterenol infusion was felt to be less desirable in ischemic heart failure. The goal was to devise a compound with a reduced risk of arrhythmia by identifying compounds with less effect on increasing heart rate than the parent compound isoproterenol. The clinical target for this drug design was ischemic heart failure because, at the time, there was little available to treat acute heart failure of any form, and ischemic heart failure was most common. In the process of modifying the structure of isoproterenol, dobutamine was identified and remains to this day, one of the few drugs available to treat acute heart failure. Albeit imperfect, dobutamine continues to be a mainstay in the management of acute congestive heart failure and has been for 35 years. …