Synthesis and Pharmacological Evaluation of Novel Nitrobenzenic Thromboxane Modulators as Antiplatelet Agents Acting on Both the Alpha and Beta Isoforms of the Human Thromboxane Receptor

Abstract

Thromboxane A(2) (TXA(2)) is an arachidonic acid metabolite involved in pathologies such as stroke, myocardial infarction, and atherosclerosis. Consequently, the design of TXA(2) receptor (TP) antagonists remains of great interest in cardiovascular medicine. The actions of TXA(2) are mediated by its specific G-protein coupled receptor of which two alternative spliced isoforms, TPalpha and TPbeta, have been described in humans. In this study, we report the synthesis of a series of original N-alkyl-N'-[2-(cycloalkyl, alkylaryl)-5-nitrobenzenesulfonyl]urea and N-alkyl-N'-[2-(alkylaryl)-5-nitrobenzenesulfonyl]-N' '-cyanoguanidines and outline their pharmacological evaluation using the individual TPalpha and TPbeta isoforms. Among compounds analyzed, several of them exhibited greater affinity and/or functional activity for either TPalpha or TPbeta. The most promising molecules were also found to be antiplatelet agents. From the present results, structural features involved in isoform selectivity can be proposed, and thereby several lead compounds have been identified for the further development of selective TP isoform antagonists.

Enhanced airway smooth muscle cell thromboxane receptor signaling via activation of JNK MAPK and extracellular calcium influx

“…TXA 2 synthase inhibitors and TP receptor antagonists have been developed as anti-asthma drugs, and demonstrated to improve TP receptor-induced airflow limitation and bronchial hyperresponsiveness (Hanson et al, 2005;Ishimura et al, 2008;McKenniff et al, 1991). However, the signaling pathway responsible for modulation of TP receptor mediated airway hyperresponsiveness to TXA 2 is not clear.…”

Preparation and Bio-evaluation of 99mTc-carbonyl Complex of Ursodeoxycholic Acid for Heptobiliary Imaging

“…At 2 h post injection, the majority of tissues and organs showed significant decreased in 99m Tctricarbonyl UDCA uptake. On the other hand, lung and intestine showed significant increase in 99m Tc-tricarbonyl UDCA uptake [20]. There were gradual increase of liver and intestine uptakes through experiment time points, which indicated that the clearance mechanisms of these complexes were through the renal and hepatobiliary path way where the urine was increase from13.5 ± 0.005 at 30 min into 45.57 ± 0.33 at 2 hr.…”

Chromatographic Separation and Utilization of Labeled 99mTc-Valsartan for Cardiac Imaging

“…The formed complex remained stable with increasing the amount of valsartan up to10 mg. So the optimum amount of valsartan was kept at 2 mg [13,14].…”