Design, synthesis and biological evaluation of thromboxane A2 antagonists (TXA2)

Duration

1999-2004

Keywords

organic synthesis,pharmacology, thromboxane A2

Description

Thromboxane A2 (TXA2) is a cellular lipidic mediator resulting from metabolisation of arachidonic acid by cyclooxygenases. This prostanoid is a potent inducer of platelet aggregation, a constrictor of vascular and bronchial smooth muscles, and a stimulator of smooth muscle cells proliferation. Due to these biological properties, TXA2 is implicated in several pathologies such as myocardial infarct and bronchial asthma. Actually, high TXA2 concentrations have been measured in these pathologies. Thus molecules combining dual activity as thromboxane synthase inhibition and TXA2 receptor have a great therapeutic interest. Moreover, it has been demonstrated that drugs combining this dual activity reduce the severity of myocardial infarct and bronchial asthma. For many years, our department is involved in the design, synthesis and pharmacological evaluation of original molecules ( 70) structurally related to torasemide, as TXA2 modulators. Most of these molecules, targeting TXA2, are nitrobenzene sulfonylureas. Among this series, two molecules showing a high affinity for the human platelet TXA2 receptor were selected: BM-567 (IC50 : 1.1 nM) and BM-573 (IC50 : 1.3 nM). Both molecules have anti-aggregatory potency and are able to relax rat aorta and guinea pig trachea smooth muscles precontracted by a TXA2 receptor agonist (U-46619). Moreover, we showed that these molecules completely inhibit platelet TXA2 production at 1 µM. BM-573 has been investigated in an original porcine model of myocardial infarction induced by topical application of ferric chloride to the left anterior descending coronary artery. BM-567 was investigated in a bronchial asthma model induced by ovalbumin in passively sensitized guinea pigs. We could conclude from these studies that BM-567 and BM-573 open new perspectives in the treatment of severe pathologies such as bronchial asthma and cardiovascular disorders, respectively.

Research unit(s)

• Department of Pharmacy (MPA)

Research theme(s)

• Pharmacological evaluation of drug candidates

Staff (finished contracts)

Chairperson(s)
Bernard MASEREEL	Leader	081/724338
Research staff
Stéphanie ROLIN	Researcher

Publications (41)

Papers

Scientific reviews

PHD theses

Student theses

Collaborations

• ULG, Chimie Pharmaceutique
• Institut de Pathologie et de Génétique

Contracts

• FUNDP - FNRS
• Communauté française