Key Words: Wy 27569-Calcium entry blockade-TXA2 synthetase inhibition.Long-term clinical studies (1 1) have shown that despite the reduction in the incidence of vascular complications such as cerebrovascular and renal disease in patients treated for hypertension, there is generally no reduction in the incidence of myocardial infarction, a major cause of morbidity and mortality. It is known that occlusive vascular episodes play a major role in the pathophysiology of ischaemic heart disease, and drugs aimed at reducing or preventing platelet clumping and thrombus formation are now widely used. The rationale for this treatment lies in the known contribution of the eicosanoids thromboxane (TXA2) and prostacyclin (PGI2) to plateletvessel wall interactions in thrombus formation. TXA2 promotes platelet aggregation and is a vasoconstrictor, whereas PG12 has anti-aggregatory effects and is a vasodilator.Wy 27569 was developed as a compound that combined antihypertensive activity due to calcium entry blockade (CEB) with inhibition of the enzyme responsible for the formation of TXA2, thromboxane synthetase. Such a combination would hopefully be useful both as an antihypertensive and antianginal and also have therapeutic indications where the presence of occlusive vascular disease was either demonstrated or was a likely risk. Structurally, Wy 27569 incorporates a dihydropyridine (DHP) moiety that has been shown to possess CEB properties and an imidazole moiety shown to inhibit thromboxane synthetase.
CHEMISTRYWy 27569 and related analogues can be prepared by a number of synthetic methods (1,2); the best of these is outlined in Fig. 1. Wy 27569 hydrochloride is a pale yellow microcrystalline powder with a melting point of 223-225'C and solubility in water of 5.6 mg/ml at 20°C.
Key Words: Wy 27569-Calcium entry blockade-TXA2 synthetase inhibition.Long-term clinical studies (1 1) have shown that despite the reduction in the incidence of vascular complications such as cerebrovascular and renal disease in patients treated for hypertension, there is generally no reduction in the incidence of myocardial infarction, a major cause of morbidity and mortality. It is known that occlusive vascular episodes play a major role in the pathophysiology of ischaemic heart disease, and drugs aimed at reducing or preventing platelet clumping and thrombus formation are now widely used. The rationale for this treatment lies in the known contribution of the eicosanoids thromboxane (TXA2) and prostacyclin (PGI2) to plateletvessel wall interactions in thrombus formation. TXA2 promotes platelet aggregation and is a vasoconstrictor, whereas PG12 has anti-aggregatory effects and is a vasodilator.Wy 27569 was developed as a compound that combined antihypertensive activity due to calcium entry blockade (CEB) with inhibition of the enzyme responsible for the formation of TXA2, thromboxane synthetase. Such a combination would hopefully be useful both as an antihypertensive and antianginal and also have therapeutic indications where the presence of occlusive vascular disease was either demonstrated or was a likely risk. Structurally, Wy 27569 incorporates a dihydropyridine (DHP) moiety that has been shown to possess CEB properties and an imidazole moiety shown to inhibit thromboxane synthetase.
CHEMISTRYWy 27569 and related analogues can be prepared by a number of synthetic methods (1,2); the best of these is outlined in Fig. 1. Wy 27569 hydrochloride is a pale yellow microcrystalline powder with a melting point of 223-225'C and solubility in water of 5.6 mg/ml at 20°C.
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