Design of an antithrombotic-antihypertensive agent (Wy 27569). Synthesis and evaluation of a series of 2-heteroaryl substituted dihydropyridines

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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“…Wy 27569 and related analogues can be prepared by a number of synthetic methods (1,2); the best of these is outlined in Fig. 1.…”

Section: Chemistrymentioning

confidence: 99%

Wy 27569, A Novel Antihypertensive Agent with Antithrombotic Properties

Middlefell

Ennis

Ward

1990

Cardiovascular Drug Reviews

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“…1,4-DHPs are an important class of Ca 2+ channel blockers and are also known to be effective cardiovascular agents for the treatment of hypertension. Apart from these activities, DHPs are found to be as platelet-activity factor antagonists [8], calcium antagonists [9], antihypertensives [10], cerebral antischemic activity in the treatment of Alzheimer's disease and chemosensitizer acting in tumor therapy. Although the synthesis of pyrazolo-1,4-dihydropyridines using expensive starting material like 3-methyl-4,5-dihydro-1H-pyrazol-5-amine or 3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-amine, has considerably contributed to the development of new pyrazolo-1,4-DHPs [11][12][13][14][15], yet, the achieved molecule remains beyond the reach of most manufacturers, as it involves the usage of expensive starting material.…”

Section: Introductionmentioning

confidence: 99%

Catalyst free, one-pot, facile synthesis of novel pyrazolo-1,4-dihydropyridine derivative form pyranopyrazoles

et al. 2014

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“…The title compounds under investigation are also associated with the structural aspects of dihydropyridine (DHP) and quinoline moieties. The chemical modifications carried out on the DHP ring [7] such as the presence of different substituents [8] or heteroatoms [9] have allowed expansion of the structure activity relationship and afforded some insights into the molecular interactions at the receptor level. 1,4-DHPs are well known because of their pharmacological profiles [10,11].…”

Section: Introductionmentioning

confidence: 99%