Soft drugs. XX. Design, synthesis, and evaluation of ultra-short acting beta-blockers.

A new type of ultra-short acting beta-blocker which might prove advantageous in treating acute arrhythmias was designed, synthesized and investigated. Based on the soft drug "inactive metabolite approach," the inactive phenylacetic acid metabolite of both metoprolol and atenolol was reactivated by esterification with sulfur-containing aliphatic alcohols. Since the sulfur-containing moieties are labile to the ubiquitous esterases, the new compounds should be inactivated by a one step enzymatic cleavage back to the inactive phenylacetic acid derivative. Pharmacological and pharmacokinetic profiles of the new compounds were evaluated in rats and rabbits. Isoproterenol-induced tachycardia was inhibited with short-term infusion of each compound. This tachycardia blocking effect rapidly disappeared upon termination of infusion, while beta-blocking activity was 2-4-fold longer after comparable doses of the short-acting beta-blocker, esmolol. The rapid recovery from the beta-receptor blockade is believed due to fast hydrolysis of the soft drugs in the body. This is supported from in vitro results showing the t1/2 of esmolol is about 10-fold longer than the new soft drugs in rat, rabbit, dog and human blood. Hydrolysis studies in phosphate buffered solutions indicated that the esters are labile to base-catalyzed hydrolysis. However, the relative t1/2 values measured in biological media compared to phosphate buffered solution clearly support rapid enzymatic cleavage of the soft drugs. Interestingly, one of the soft beta-blockers, the sulfonyl ester derivative, showed a unique property of exhibiting good beta-receptor blocking activity without significant hypotensive action.