Derivatives of Bis-Aldonic Acid Amides and Their Anticoagulant and Antithrombotic Properties

Abstract

Aprosulate sodium was the first representative of a new class of synthetic polyanions showing antithrombotic efficacy in different animal models. In several clinical trails (Phase I) in human volunteers aprosulate demonstrated anticoagulant properties, too. Searching for other active substances of similar structure, a series of bis-aldonic acid amides were synthesized. These compounds exhibited interesting antithrombotic and anticoagulant activities. The pharmacodynamic activities of the compounds LW 10121, LW 10125, LW 10114, 10244, and LW 10168 are summarized in this article. These substances prolonged the APTT to 150% of the blank values at concentrations of 1.5 to 13.5 micrograms/mL. The thrombin time and anti-Xa test were only slightly influenced by concentrations up to 100 micrograms/mL. All compounds were investigated in a jugular vein hemostasis model in rats to examine their antithrombotic potential. They all had an antithrombotic activity lower than aprosulate, except compound LW 10121, which seemed to be a little more active. The subcutaneous injection of 10 mg/kg LW 10121 resulted in a longer duration of action than aprosulate and heparin. On the basis of the chemical structure and the profile of action, it is assumed that the new compounds may possess the same mode of action as aprosulate, but the mechanism of action may be different from heparin and low molecular weight heparins.

Synthetic Oligosaccharides as Heparin-Mimetics Displaying Anticoagulant Properties

“…These results encouraged researchers to synthesize some other derivatives with close structural resemblance to aprosulate sodium [62] (Table 6). Both the sugar units and the chain length were varied.…”

Synthesis and structural investigations on R2 Sn(IV)‐D‐aldonic acid complexes (R = methyl; butyl). Their effect on a new toxicity test organism, Liza saliens (Osteichthyes, Mugilidae): a histological study

“…[2] As far as diorganotin(IV) moieties with acidic carbohydrates derivatives are concerned, it has been shown that the sugar often acts as dianionic chelating ligand, via carboxylate and suitable alkoxidic groups, even at low pH. [4 -6] Aldonic acids are a class of acidic carbohydrates derivatives used in industrial, [7,8] medical [9,10] and cosmetic [11 -13] applications or as intermediates in organic synthesis. [14 -16] An IR and Mössbauer solid-state study of a hydrated dibutyltin(IV) gluconate compound (Bu 2 SnGlun · H 2 O) and a potentiometric and 13 C NMR solution investigation of Me 2 SnGlun have been already reported.…”

Effects of Aprosulate, a Novel Synthetic Glycosaminoglycan, on Coagulation and Platelet Function Parameters: A Prospective, Randomized Phase I Study

“…Aprosulate (Luitpold Pharma Munich, Germany) has a molecular weight of 2,388 d. In vitro and ex vivo it prolongs activated partial thromboplastin time (aPTT), thrombin time, and Heptest (Haemachen Int., St. Louis, MO, USA) in different animal and human plasmas (5)(6)(7)(8). In contrast to UFH and LMWH it has very little anti-IIa-and no antiXa-effect.…”

“…Bislactobionic acid amides as aprosulate, a new class of fully synthesized highly sulfated synthetic glycosaminoglycans were developed with the aim to obtain antithrombotic drugs with a low risk of bleeding in comparison with unfractionated heparin (UFH) or low molecular weight heparins (LMWHs) (1)(2)(3)(4). Aprosulate (Luitpold Pharma Munich, Germany) has a molecular weight of 2,388 d. In vitro and ex vivo it prolongs activated partial thromboplastin time (aPTT), thrombin time, and Heptest (Haemachen Int., St. Louis, MO, USA) in different animal and human plasmas (5)(6)(7)(8). In contrast to UFH and LMWH it has very little anti-IIaand no anti-Xa-effect.…”

“…Aproxulate has shown dose-dependent antithrombotic effects in different arterial and venous animal models of thrombosis at doses ranging from 1 to 30 mg/kg (5,8,(14)(15)(16)(17)(18). Injection of protamine sulfate partially reversed the antithrombotic effects of aprosulate (16).…”