Antithrombotic activity

These agents interact directly with thrombin and do not require antithrombin to have antithrombotic activity. They are capable of inhibiting both circulating and clot-bound thrombin, which is a potential advantage over UFH and the LMWHs. They also do not induce immune-mediated thrombocytopenia and are widely used for the treatment of HIT. 

The higher antiaggregatory and antithrombotic activity can be explained by the fact that the NO-release from sydnonimines can occur in the blood plasma independently of the presence of activating cellular cofactors. The antithrombotic activity of C89-4095 has been reported to be inhibited by oxyhemoglobine, thus demonstrating a clear sGC- and cGMP-mediated mechanism for platelet inhibition. C4144 90 showed a... 

Azaurolic acid 137 is a compound that displays antithrombotic activity and that, both in solution and in the solid state, releases N2O, which is the product of dimer-ization/dehydration of HNO, giving the stable compound 138 (R=Ri=CH3, Scheme 6.27). This latter product also displays anthitrombotic activity [173]. These findings prompted the synthesis ofa series of 1,3,4-triazol-l-oles 138 which were obtained by cyclisation of the parent oximes 139 in aqueous alkali. 

All products showed antithrombotic activity the most potent was found to be the dimethyl derivative, which also significantly decreased blood pressure when administered orally to spontaneously hypertensive rats. Possible involvement of NO in this action was suggested but not demonstrated. 

As a typical example of a 6-heteroarylsubstituted dihydropyridazinone exhibiting antithrombotic activity motapizone, NAT 05-239 (63) (CAS 90697-57-7) may serve [96], Compound CCI 17810 (64) (CAS 76283-03-9) bearing a substituted phenyl moiety at C-6 of the pyridazine system has been shown to inhibit potently in vitro human platelet aggregation (induced by collagen, ADP, thrombin or arachidonic acid) with EC50 values in the range of 0.5-10/rg/ml [245], ... 

Antithrombotic activity has been claimed also for some related fully unsaturated pyridazinones [208, 210, 241,244, 251]. Many of these compounds were found to exhibit additionally antihypertensive, positive inotropic, antiallergic or anti-inflammatory activity. Pyridazinones of type (60) and (65) have been reported recently to enhance the activity of antithrombotic phenylacetonitrile derivatives [253]. 

In addition to the hydrazinopyridazine derivatives discussed above, a wide variety of pyridazinones and 4,5-dihydropyridazinones exhibit interesting antihypertensive activity. Some selected examples of such compounds claimed in patents are given in formulae (78) [18-20,51,111,116,129,311-335], (79) [169,336], (80) [169,337], (81) [338-341], (82) [52-56,59,60, 127,342-357], (83) [358-362], and (84) [363-365], For many of these compounds also cardiotonic and/or antithrombotic activity has been claimed (compare Part 1 of this review [1]). 

Pharmacology The antithrombotic activity is the result of antithrombin III (ATIII)-mediated selective inhibition of Factor Xa. Neutralization of Factor Xa interrupts the blood coagulation cascade and thus inhibits thrombin formation and thrombus development. 

Thio-p-D-xylopyranosides that contain aromatic aglycons, such as Beciparcil (246, Fig. 24), and related analogues have potent antithrombotic activity in... 

E. Bozo, A. Medgyes, S. Boros, and J. Kuszmann, Synthesis of 4-substituted phenyl 2,5-anhydro-1,6-dithio-a-gluco- and -a-guloseptanosides possessing antithrombotic activity, Carbohydr. Res., 329 (2000) 25-40. 

Rishirihde B (57) (Figure 7.10) was isolated by Iwaki and co-workers from Strep-tomyces rishiriensis OFR-1056 [24], and this compound exhibits antithrombotic activity through selective a2-macroglobuhn inhibition. Allen and Danishefsky synthesized 57 utiHzing regioselective Diels-Alder reaction of the quinodimethide... 

The nitrosoimine derivative RE 2047 (45) in combination with pentoxifylline demonstrates potent antithrombotic activity <95AP(328)71). Other sydnones with pharmacological activity include derivatives of the general formulas (46) and (47). These agents were shown to have antiinflammatory, analgesic, and antipyretic activity <95JPS263). 3-Arylsydnones have been intensively studied because... 

A.K. Sim, M.E. Cleland, A.B. Pottage, Y. Matsumura, T. Nakano, The antithrombotic activity of AFP-07, a potent novel prostacyclin analogue, 10th Int. Conf. Prostaglandins Rel. Comp., Vienna (1996). 

From a series of sulfated bis-aldonic acid amides with different alkyl spacer length, compound 34 was chosen for further evaluation as an antithrombotic. This compound was synthetically available in four steps from lactobionic acid (Scheme 7). Compound 34 had relatively high APTT values (42 U/mg) and antithrombotic activity, both of which decreased gradually when the number of methylene groups in the spacer was increased. It was thought to act via HCII and multiple sites in the intrinsic pathway of the coagulation cascade [64]. 

A number of 1-substituted 2(l//)-pyrazinone derivatives show antithrombotic activity as selective inhibitors of the tissue Factor Vila complex <2003BML23I9> and were examined as mast cell tryptase inhibitors <2004BML48I9>. As a curious effect, dihydropyrazines proved to show DNA strand-breakage activity <2005CPB1359>. 

Finally, the hetero polysaccharide hexagluconylhexasaminoglycan sulfate was identified as an anticoagulant and antithrombotic material compared to heparin by Sederel and coworkers [521], Derivatives of the polysaccharide dextran containing sulfate, sulfonate or carboxylic groups gave antithrombotic activity due to the presence of these charged groups [483, 522-525],... 

In addition to the presence of natural coumarin derivatives, phytochemical analysis found that dong quai also contains ferulic acid and osthole as ingredients. Ferulic acid was reported to have antithrombotic activity (38). Similarly, study using the closely related Angelica pubescens also found osthole to be antithrombotic (39). These two chemical constituents exert their antithrombotic effects by interfering with different pathways responsible... 

Activated clotting time (ACT) and activated partial thromboplastin time (aPTT) are relatively unaffected by LMWH. Anti-Xa activity can be used to monitor anticoagulation activity, but this is expensive and time-consuming and is seldom indicated. Although protamine has some effect on LMWH, about 60-80% of the antithrombotic activity will persist. This is because of the reduced protamine binding to these drugs and because only the anti-IIa activity is completely reversed whereas anti-Xa activity is only partially neutralised. 

Fonseca, R. J., Oliveira, S. N., Melo, F. R., Pereira, M. G., Benevides, N. M., and Mourao, P. A. (2008). Slight differences in sulfation of algal galactans account for differences in their anticoagulant and venous antithrombotic activities. Thromb. Haemost. 99, 539-545. 

Garlic (Allium sativum) is thought to have several beneficial cardiovascular effects, such as lowering blood pressure and serum lipid, and antithrombotic activity. Garlic oil has been reported to interrupt thromboxane synthesis, thereby inhibiting platelet function. 

Wang, H.X. and Ng, T.B., Natural products with hypoglycemic, hypotensive, hypocholesterolemic, anti-atherosclerotic and antithrombotic activities, Life Sci., 65, 2663-2677, 1999. 

Herbert JM, Dol E Bemat A, Falotico R, Lale A, Savi P The antiaggregating and antithrombotic activity of clopidogrel is potentiated by aspirin in several experimental models in the rabbit. Thromb Haemost 1998 80 512-518. 

The compounds potently inhibit factor Xa in vitro with reversible binding kinetics and are able to inhibit not only free but also prothrombinase-bound factor Xa (Ki 41 nM, 0.1 I nM, and 0,5 nM, respectively) (58-60), In contrast, no direct effect on platelet aggregation has been described (60-62), Antithrombotic activity in arterial and venous thrombosis models has been demonstrated and it has a reduced effect on hemorrhage in comparison to standard therapy (58,60,63). Factor Xa inhibitors are able to reduce the endogenous thrombin potential in platelet-poor as well as in platelet-rich plasma (64,65). Thus, thrombin generation seems to be a suitable biomarker for clinical evaluation and has been evaluated in phase I studies (66,67). 

This type of matrix has been evaluated with limited success. The chief drawbacks include poor control of drug release, particularly for drugs that are water-soluble, and poor biocompatibility due to matrix swelling in preclinical animal studies. Hydrogels comprising heparin (37) or poly(EO) (38,39) in the very top layer of DES coating may have local antithrombotic activity. 

Lead optimization of a series of oxazolidinone derivatives led to the discovery of rivaroxaban l.9 Basic screening tests for this compound demonstrated a highly potent and selective, direct inhibitory action on FXa (IC o = 0.7 nM, Kj = 0.4 nM), excellent in vivo antithrombotic activity and a good pharmacokinetic profile in preliminary studies in animal models (Table 1). The lipophilic chlorothiophene moiety in rivaroxaban is responsible for a decrease in unbound fraction and aqueous solubility and attempts to identify less lipophilic replacements by broad variation were not successful. 

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