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A novel series of 4-[N-methyl-N-[(E)-3-[4-(methylsulfonyl)phenyl]-2- propenoyl]amino]benzenesulfonamides has been prepared and evaluated as membrane-bound phospholipase A2 inhibitors. A structure-activity relationship study indicated that the optimum potency was realized with the N-(phenylalkyl)piperidine derivatives 3 and 4. These compounds inhibited the liberation of arachidonic acid from the rabbit heart membrane fraction with IC30 values of 0.028 and 0.009 microM, respectively. Several compounds (3, 4, and 28), which proved to be potent inhibitors in vitro, significantly reduced the size of myocardial infarction in coronary occluded rats by iv administrations prior to the ligation. N-(1-Benzyl-4-piperidinyl)-4-[N-methyl-N-[(E)-3-[ 4-(methylsulfonyl)phenyl]-2-propenoyl]amino]-benzenesulfonamide (3, ER-3826), which showed the protective in vivo effects at doses higher than 0.3 mg/kg iv, was finally chosen as a leading candidate.

Abstract-Postsynaptic a-receptor blocking properties of E-643 were studied in vivo and in vitro and compared with these same properties of phentolamine and phenoxy benzamine.In anesthetized rats, E-643 (i.v.) attenuated pressor response to adre naline dose-dependently and an adrenaline-reversal was seen with large doses. The in vivo a-adrenoceptor blocking effect of E-643 was 3.4 times more potent than that of phentolamine.On the other hand, hypotensive action of E-643 was 9.4 times more potent than that of phentolamine.In the isolated rabbit aorta, E-643 blocked nor adrenaline-induced contraction of the aorta with a parallel shift of the dose-response curve to the right. The pA2 values for E-643 and phentolamine were 8.60 and 7.65, respectively. The a-blocking effect of E-643 was reversible. E-643 protected a receptors against irreversible inhibition by phenoxybenzamine.E-643 neither exhibited significant blocking effects on K--, Bat and angiotensin-induced contractions of the aorta nor caused relaxation of the aorta contracted by Cat+. These data suggest that E-643 is a specific and competitive inhibitor of noradrenaline at the a-adrenoceptors. E-643 is one of the twenty-eight aminodimethoxyquinazoline derivatives which were synthesized and pharmacologically screened in our laboratories. In the course of the screening, E-643 was found to have potent activities in lowering blood pressure in anesthetized rats as well as antagonizing contractile response of the isolated rat vas deferens to /-noradrenaline (Noradr).Long-lasting reduction in blood pressure in spontaneously hypertensive rats (SHR) and reversal of the pressor response to intravenously administered adrenaline in both nor motensive and hypertensive rats after an oral administration of E-643 were reported by Igarashi et al. (1, 2). The hypotensive effect of E-643 in SHR was evident with oral doses over 0.1 mg/kg (2).The experiments reported herein were a quantitative evaluation of the a-adrenoceptor blocking activity of E-643 in vivo and in vitro and clarification of the properties of the a-blocking action of E-643 was made.

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