Yang H S, Wu W M, Bodor N
J. Hillis Miller Health Center, College of Pharmacy, University of Florida, Gainesville, 32610, USA.
Pharm Res. 1995 Mar;12(3):329-36. doi: 10.1023/a:1016283930696.
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.
设计、合成并研究了一种新型超短效β受体阻滞剂，其在治疗急性心律失常方面可能具有优势。基于软药的“无活性代谢物方法”，美托洛尔和阿替洛尔的无活性苯乙酸代谢物通过与含硫脂肪醇酯化而重新激活。由于含硫部分对普遍存在的酯酶不稳定，新化合物应通过一步酶促裂解回到无活性的苯乙酸衍生物而失活。在大鼠和兔子中评估了新化合物的药理学和药代动力学特征。短期输注每种化合物可抑制异丙肾上腺素诱导的心动过速。输注终止后，这种心动过速阻断作用迅速消失，而在给予相当剂量的短效β受体阻滞剂艾司洛尔后，β受体阻断活性持续时间长2至4倍。β受体阻滞剂作用的快速恢复被认为是由于体内软药的快速水解。体外结果支持这一点，结果显示艾司洛尔在大鼠、兔子、狗和人血液中的t1/2比新软药长约10倍。在磷酸盐缓冲溶液中的水解研究表明，酯对碱催化的水解不稳定。然而，与磷酸盐缓冲溶液相比，在生物介质中测得的相对t1/2值清楚地支持了软药的快速酶促裂解。有趣的是，其中一种软β受体阻滞剂，即磺酰酯衍生物，表现出一种独特的特性，即具有良好的β受体阻断活性而无明显的降压作用。
