Amosulalol

Abstract

The most important hemodynamic disturbance in patients with hypertension is an increase in peripheral vascular resistance due to arteriolar constriction (8). Accordingly, the most desirable way to lower blood pressure is to decrease peripheral vascular resistance without adversely affecting cardiac function.Both aand P-adrenoceptor antagonists are effective drugs for the treatment of hypertension. Although or-adrenoceptor antagonists decrease the peripheral resistance through attenuation of the sympathetic vasoconstriction, especially at the arterioles, most of these drugs have limited use because of unacceptable reflexly mediated cardiovascular side effects. On the other hand, P-adrenoceptor antagonists are less effective as hypotensives and have a slower onset of action than cx-antagonists. They may even cause an initial increase in peripheral vascular resistance. A combination of an a-antagonist with a @-antagonist is theoretically beneficial because a-blockade eliminates peripheral vasoconstriction and P-blockade overcomes reflex cardiac acceleration and renin release. In fact, such a cbmbination has resulted in some clinical studies in good control of high blood pressure with few side effects (12,26).Based on the above considerations, the concept of combining the activities of aand P-adrenoceptor blockade in a single molecular entity is logical and should lead to an effective treatment of hypertension. Takenaka et al. (46) and Fujikara et al. (9) found that a series of arylethanolamines derived from benzenesulfonamide possessed both a-and /3-adrenoceptor blocking activities in different ratios. Amosulalol was selected from these derivatives, as it blocked or,-and p,-adrenoceptors almost to the same extent and showed beneficial antihypertensive activity in animals (46). CHEMISTRY Amosulalol hydrochloride (YM-09538) is (*)-5-[ I -hydroxy-2-[[2-(o-methoxyphenoxy)ethyl]amino]ethyl]-2-methylbenzenesulfonamide hydrochloride (Fig. 1). It was synthesized and patented by Imai and co-workers at Central Research Laboratories of Yamanouchi Pharmaceutical Co. Ltd. (19). Synthesis pathways of amosu-AMOS ULA LOL SO2 NH2 CH~-&H-CHZ -NH-CH2 -CHz -0 *HCI OCH3 OH FIG. 1. Structure of amosulalol hydrochloride (YM-09538).lalol and 14C-amosulalol and resolution of its optical isomers were reported (2,lO). Amosulalol is a white, odorless crystalline powder with a bitter taste. It has a molecular weight of 416.93 (C18H24N20SS.HC1) and a melting point of 158-162°C. The substance is soluble in methanol, sparingly soluble in water (1.5 g/ 100 ml) and in absolute ethanol, very slightly soluble in acetone, and practically insoluble in ether, chloroform, and benzene. The pKal for the secondary amine and pKa2 for amosulalol are 7.72 and 10.04, respectively. Its n-octanol-water partition coefficient at pH 7.0 is 2.70, which is lower than the values reported for propranolol or labetalol (54). ANIMAL PHARMACOLOGY Zn Vitr5 a-and P-Adrenoceptor Blocking ERectsThe activity of amosulalol as an antagonist of two subtypes of aor P-adrenoceptors wa...