Hydantoin prostaglandin analogues, potent and selective inhibitors of platelet aggregation

Caldwell, A. G.; Harris, Christopher; Stepney, Ray; Whittaker, Norman

doi:10.1039/c39790000561

Cited by 26 publications

(6 citation statements)

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“…It is a hydantoin prostaglandin analogue which is chemically stable and potentially orally active. In addition, it has been reported to have a selectivity of action, causing less vasodilatation than PGE, in experimental animals, while having approximately 14 times the potency of PGE, on human platelet-rich plasma (Caldwell et al, 1979(Caldwell et al, , 1980.…”

Section: Discussionmentioning

confidence: 99%

“…BW 245C is a hydantoin prostaglandin analogue (Figure 1) which is a vasodilator and an inhibitor of platelet aggregation. It may be relatively selective towards platelets (Caldwell et al, 1979(Caldwell et al, , 1980 but is otherwise qualitatively similar to epoprostenol (PGI2). PGI2 has considerable therapeutic potential (Moncada & Vane, 1981) but it is stable only at basic pH and is not active by mouth.…”

Section: Introductionmentioning

confidence: 99%

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Cardiovascular and platelet effects in man of BW 245C, a stable mimic of epoprostenol (PGI2).

Ma¹,

Ritter²,

Shepherd³

et al. 1983

Brit J Clinical Pharma

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1 BW 245C is a stable hydantoin prostaglandin analogue with a biological action similar to epoprostenol (PGI2). 2 Intravenous BW 245C (1,2 and 4 ng kg‐1 min‐1) produced a progressive increase in heart rate and pulse pressure in four healthy male volunteers. 3 These changes in heart rate and pulse pressure were accompanied by reduced ex vivo platelet aggregation to submaximal concentrations of ADP. 4 In man, BW 245C has a profile of action and potency similar to PGI2. However, it has a longer duration of action than PGI2.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cardiovascular and platelet effects in man of BW 245C, a stable mimic of epoprostenol (PGI2).

Ma¹,

Ritter²,

Shepherd³

et al. 1983

Brit J Clinical Pharma

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“…The saturated analogue (7) was obtained by hydrogenation of the unsaturated ester (3) over palladium-charcoal and transformation of the resulting compound (12) (see Scheme 3) by the methods described for Scheme 1. Compound (7) proved to be about 7 times more active than (6).…”

Section: Resultsmentioning

confidence: 89%

“…It is known that natural prostaglandins are inactivated rapidly in the body by the 15-hydroxydehydrogenase enzyme which oxidises the important secondary hydroxy group at C-15 to a ketone." It was assumed that this would occur with 8,10,12triazaprostaglandin analogues such as (6), (7), and (ll), and indeed such compounds, whilst possessing short lived bronchodilator activity when given intravenously, were inactive when given orally. This problem of rapid metabolic inactivation has been partially overcome in natural prostaglandins by introduction of a 15-methyl group, thus preventing oxidation.20*21 It appeared to be a relatively simple task to introduce a 15-methyl group into our compounds by treatment of compounds such as (8) or (4) with methylmagnesium iodide or methyl-lithium.…”

Section: ( 7 )mentioning

confidence: 99%

“…The aqueous layer was adjusted to pH 2 and extracted with ether (3 x 100 ml). Evaporation of the combined ex tracts gave 1 1-(6-Carboxyhexyf )-2-( 3-hydroxynonyl)-4-methyl-1,2,4-triazolidine-3,5-dione (7).-This compound was obtained as a viscous gum in 89% yield by -hydrolysis of its ester using the method described for the preparation of compound (6) ( 13 mol) and oct-1-en-3-one (see below) (14.8 g, 0.12 mol) in dioxane (200 ml) was treated with 40% methanolic benzyltrimethylammonium hydroxide (1 5 drops) and heated under reflux for 24 h. The mixture was allowed to cool, poured into water (300 ml), and extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with brine (2 x 100 ml) and dried.…”

Section: ( 7 )mentioning

confidence: 99%

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The synthesis of 8,10,12-triazaprostaglandin analogues: 1,2,4-triazolidine-3,5-dione derivatives

Adams¹,

Barnes²,

Cassidy³

et al. 1984

J. Chem. Soc., Perkin Trans. 1

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In the search for active, more selective prostaglandin analogues, the synthesis of 8,10,12-triazaprostaglandin analogues t has been achieved from readily available 4-methyl-l,2,4-triazolidine-3,5-dione. The general approach involved introduction of the a-and o-side-chain as entire units by step-wise N-alkylation. The problems encountered with this approach of competing N-and O-monoand di-alkylation were overcome, eventually, such that judicious choice of the initial mono-N-alkylation step enabled the synthesis of analogues incorporating wide variations in the a-and a-side-chain. Important structural modifications included introduction of unsaturation into the a-side-chain at the 5,6-position and of methyl groups into the a-side-chain at the 15-and 16-position as exemplified by the synthesis of 1 -[ (Z)-6-carboxyhex-2-enyl] -2-(3hydroxy-3,4-dimethyloctyl) -4-methyl-l,2,4-triazolidine-3,5-dione (1 9). The stable triazaprostaglandin analogues were synthesized as racemic compounds but, nevertheless, compound (1 9) possessed bronchodilator activity of a similar order to that of the natural prostaglandins PGE, and PGE,.

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Agents Acting on Prostanoid Receptors

Jenkins

Humphrey

Coleman³

2003

Burger's Medicinal Chemistry and Drug Discovery

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The prostaglandins and thromboxanes comprise a family of C 20 fatty acids, known as the prostanoids. They are primarily synthesized from arachidonic acid and exert a multitude of physiological and pathophysiological actions through the activation of membrane‐bound receptors. The current scheme of prostanoid receptor classification proposes receptors for each of the naturally occurring prostanoids and was originally based on comparisons of prostanoid receptor agonist and antagonist potencies in functional preparations. This scheme has been confirmed and expanded by the use of molecular techniques, which have led to the cloning of the known prostanoid receptors and also the discovery of a number of prostanoid receptor subtypes and isoforms. Many compounds with varying potencies and selectivities at the known prostanoid receptors have been synthesized, although few have proved highly valuable in the clinic. The use of prostanoids in clinical practice has been largely limited to those occurring naturally, where they are used predominantly as abortifacients and in the induction of labor. Several synthetic analogs have also been used for these and other purposes, including the treatment of gastric ulcers and glaucoma. Hopefully, the next few years will lead to the further discovery of new prostanoid receptor ligands that will become successful medicines.

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Hydantoin prostaglandin analogues, potent and selective inhibitors of platelet aggregation

Cited by 26 publications

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Cardiovascular and platelet effects in man of BW 245C, a stable mimic of epoprostenol (PGI2).

Cardiovascular and platelet effects in man of BW 245C, a stable mimic of epoprostenol (PGI2).

The synthesis of 8,10,12-triazaprostaglandin analogues: 1,2,4-triazolidine-3,5-dione derivatives

Agents Acting on Prostanoid Receptors

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