A stable prostacyclin-like substance produced by the medicinal leech Hirudo medicinalis

Nikonov, G I; Титова, Елена Анатольевна; Seleznev, K.G.

doi:10.1016/s0090-6980(99)00016-7

Cited by 3 publications

(4 citation statements)

References 7 publications

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“…Arachidonic acid Nikonov et al (1999) As can be seen from Table·1, the PGs formed in invertebrates appear to fall into two categories, namely novel PGs only found in invertebrates, and the classical PGs (e.g. PGE 2 , PGD 2 etc.)…”

Section: Prostaglandins In Non-insectan Invertebratesmentioning

confidence: 99%

“…Overall, however, there was no convincing evidence that the compounds formed were identical to classical PGs. Similarly, leeches (Hirudo medicinalis) are said to produce a PGI 2 -like substance (Nikonov et al, 1999). Although the active substance inhibits human platelet aggregation and reacts with antiserum to 6-keto-PGF 1α , the stable breakdown product of PGI 2 , no structural data were provided.…”

Section: Table·1 Prostaglandin (Pg) Generation In Non-insectan Invermentioning

confidence: 99%

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Prostaglandins in non-insectan invertebrates: recent insights and unsolved problems

Rowley

Vogan

Taylor

et al. 2005

Journal of Experimental Biology

122

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Prostaglandins, together with thromboxanes (collectively termed prostanoids), are fatty acid derivatives of significant importance in many physiological processes. These compounds are formed following the action of cyclooxygenases (COX) and associated enzymes on C20 polyunsaturated fatty acid precursors released from phospholipids in membranes. Nearly all mammalian cell types have the biosynthetic machinery to produce at least one type of prostanoid. The same C20 fatty acid substrates can also be acted upon by lipoxygenases to produce mono-di-and trihydroxy derivatives such as leukotrienes, lipoxins and resolvins. The final route is the cytochrome P 450 pathway that can convert C20 fatty acids to hydroxylated derivatives.Collectively these compounds are called eicosanoids; the term derived from the Greek eikosi that refers to the C20 backbone in the parent fatty acid.Prostaglandins (PGs) were first discovered in the 1930s by von Euler and colleagues, who found a substance produced by the prostate gland that caused smooth muscle contraction. They christened the active substance 'prostaglandin', but it was over 30 years until the structure and mode of biosynthesis of these fatty acid derivatives became fully understood. PGs have many basic physiological functions where they act as 'local' hormones. For example, thromboxane (Tx) A 2 and prostacyclin (PGI 2 ) generated by platelets and endothelial cells, respectively, regulate the aggregatory behaviour of

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Section: Prostaglandins In Non-insectan Invertebratesmentioning

confidence: 99%

Section: Table·1 Prostaglandin (Pg) Generation In Non-insectan Invermentioning

confidence: 99%

Prostaglandins in non-insectan invertebrates: recent insights and unsolved problems

Rowley

Vogan

Taylor

et al. 2005

Journal of Experimental Biology

122

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“…The well known medicinal leech Hirudo medicinalis has powerful anticoagulant potential, primary due to hirudin, a highly specific thrombin inhibitor that also shows inhibitory action on blood plasma kallikrein. It also produces a low molecular mass prostaglandin-like compound, which inhibits the platelet aggregation stimulated by different inducers [17]. The second example is the soft tick Ornithodorus moubata, which prevents blood clotting through direct inhibition of thrombin by ornithodorin, inhibition of factor Xa by tick anticoagulant peptide (TAP) and inhibition of platelet aggregation by moubatin [18].…”

Section: Arguments For Dual Inhibitionmentioning

confidence: 99%

Dual Inhibitors of the Blood Coagulation Enzymes

Kranjc

Kikelj²

2004

CMC

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The search for an ideal anticoagulant has spanned decades and has resulted in several approaches and the identification of novel target molecules for preventing and treating thrombosis. The first group of new anticoagulant agents acting through direct inhibition of coagulation factors were inhibitors of thrombin, but factor Xa inhibitors and, most recently, factor VIIa inhibitors have become attractive candidates. The structures of thrombin, factor Xa and factor VIIa show similarities in their active sites and, for this reason, attempts have been made to develop synthetic agents containing in a single molecule inhibitory activity against two of the enzymes of the blood coagulation cascade. Such dual inhibitors are now in preclinical studies and are, potentially, new anticoagulant drugs with improved properties. The emphasis of this review will be placed on dual inhibitors of thrombin/factor Xa and factor Xa/factor VIIa. Comparison of the active sites of these enzymes is included for better understanding of the structural demands to be met in designing effective dual inhibitors.

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“…In a recent Letter to this journal we introduced a new type of low molecular weight peptidomimetic antithrombotic drugs possessing both thrombin inhibitory and GPIIb/IIIa receptor antagonistic activities in the same molecule. , Simultaneous direct inhibition of different targets in the hemostatic system by different substances is known in hematophageous animals, in which multiple inhibition of the blood coagulation enzymes and platelet activation is frequently involved . In clinical practice a combination of anticoagulant agent (e.g., warfarin (4-hydroxy-3-(3-oxo-1-phenylbutyl)-2 H -chromen-2-one), heparin, or thrombin inhibitor) and antiaggregatory drug (e.g., acetylsalicylic acid, ticlopidine (3-[(2-chlorophenyl)methyl]-7-thia-3-azabicyclo[4.3.0]nona-8,10-diene), clopidogrel (( S )-methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2- c ]pyridin-5(4 H )-yl)acetate), or GPIIb/IIIa antagonist) is frequently used to achieve an effective antithrombotic effect in patients with valvular heart disease, prosthetic heart valves, or acute coronary syndromes, in patients following myocardial infarction, or in patients undergoing thrombolysis .…”

Section: Introductionmentioning

confidence: 99%

3,4-Dihydro-2H-1,4-benzoxazine Derivatives Combining Thrombin Inhibitory and Glycoprotein IIb/IIIa Receptor Antagonistic Activity as a Novel Class of Antithrombotic Compounds with Dual Function

et al. 2008

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3,4-Dihydro-2 H-1,4-benzoxazine derivatives possessing both thrombin inhibitory and glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonistic activities were obtained by combining mimetics of the d-Phe-Pro-Arg pharmacophore of thrombin inhibitors and the Arg-Gly-Asp pharmacophore of GPIIb/IIIa receptor antagonists in the same low molecular weight peptidomimetic compound. Systematic variation of the position of substituents around the 3,4-dihydro- 2H-1,4-benzoxazine nucleus, the distance between the carboxylate and amidine moieties, together with additional substituents to fill the thrombin S 2 and S 3 pockets resulted in compounds displaying submicromolar inhibition constants ( K i) for thrombin and submicromolar IC 50 for inhibition of binding of fibrinogen to platelet GPIIb/IIIa receptor. Some of these compounds, such as 17a, 17b, 17d, and 17h possessing a well balanced activity at both targets, are a good starting point for further optimization. Incorporation of anticoagulant and platelet antiaggregatory activity in the same molecule constitutes a promising approach toward novel antithrombotic agents.

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A stable prostacyclin-like substance produced by the medicinal leech Hirudo medicinalis

Cited by 3 publications

References 7 publications

Prostaglandins in non-insectan invertebrates: recent insights and unsolved problems

Prostaglandins in non-insectan invertebrates: recent insights and unsolved problems

Dual Inhibitors of the Blood Coagulation Enzymes

3,4-Dihydro-2H-1,4-benzoxazine Derivatives Combining Thrombin Inhibitory and Glycoprotein IIb/IIIa Receptor Antagonistic Activity as a Novel Class of Antithrombotic Compounds with Dual Function

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