[Design, synthesis of novel N, N'-bis-(halogenophenyl)-4- methoxybenzene-1, 3-disulfonamides and evaluation of their anti-platelet aggregation activity].

Article

Author: Meng, Xia ; Li, Xu ; Liu, Xiu-Jie ; Wang, Xiao ; Li, Gui-Ang ; Lin, Yong-Bin

Combining the structural features of picotamide and linotroban, a series of N,N'-bis-(halogenophenyl)-4-methoxybenzene-1, 3-disulfonamides were designed and synthesized on the basic principles of drug design. The structures of target compounds were confirmed by IR, 1H NMR and HR-MS, and the in vitro antiplatelet aggregation activity was evaluated by Born turbidimetric method with adenosine diphosphate (ADP) as the platelet aggregation inducers. The assay results showed that twelve compounds (4b, 4f, 4l, 5b, 5d-5g, 5j, 5k, 5m and 5n) were found to have superior anti-platelet aggregation activities than the positive drug picotamide. The preliminary structure-activity relationship (SAR) has been explored.

01 Jul 2001·Thrombosis ResearchQ3 · MEDICINE

Antiplatelet and Anticoagulant Effects of “HN-11 500,” a Selective Thromboxane Receptor Antagonist

Q3 · MEDICINE

Article

Author: Joachim F Schenk ; Hans K Breddin ; Harald Fellier ; Piotr Radziwon

The antiplatelet and anticoagulant effect of a thromboxane receptor (TX receptor) antagonist developed by Nycomed (Linz) has been studied in a placebo-controlled double-blind phase I study. Sixteen healthy male volunteers received different single oral doses of "HN-11 500" (C(14)H(15)NO(5)S(2); 1, 10, 100, 200, and 400 mg). Eight volunteers received placebo. The washout period between each dosage applied was at least 12 days. Platelet aggregation induced by the thromboxane mimetic "U 46 619" (C(21)H(34)0(4)) and platelet adhesion to siliconized glass were significantly and dose-dependently inhibited. The effect lasted between 3 and 4 h (10 mg) and 8 h (400 mg), respectively, and correlated well with the pharmacokinetic data. Platelet aggregation seems to be more sensitive to monitor the effects of HN-11 500 on platelet function than platelet adhesion. Plasma levels of 300 ng/ml HN-11 500 probably leads to >90% inhibition of platelet aggregation. The template bleeding time slightly increased but did not exceed the normal range. Furthermore, there was a wide variation of results. There were no significant changes in platelet counts, platelet-induced thrombin generation time (PITT), and blood coagulation parameters. All doses of HN-11 500 were well tolerated. HN-11 500 is a potent TX receptor antagonist (TXRA), which inhibits either platelet aggregation or platelet adhesion, which has not yet been described. In clinical routine, TXRAs have to demonstrate the effectiveness in large clinical trials for different clinical indications and to compete with single or combined administrations of cyclooxygenase (COX) inhibitors, thienovridines, thromboxane synthase inhibitors, and GIIb/IIIa inhibitors.

01 Oct 1997·European Journal of Clinical InvestigationQ3 · MEDICINE

Cisplatin‐induced renal effects and thromboxane A₂ receptor blockade

Q3 · MEDICINE

Article

Author: WOLZT, M. ; MÜLLER, M. ; PEHAMBERGER, H. ; KORNEK, G. ; BLÖCHL‐DAUM, B. ; KLETTER, K. ; EICHLER, H. G. ; DORNER, G. T. ; BREITENEDER, H. ; STEGER, G. ; JAMES, P.

The aim of this study was to evaluate the renal protective effect of linotroban, a thromboxane A2 receptor antagonist, in 25 patients with malignant tumours scheduled for cisplatin therapy. Cisplatin was administered 1 h after the start of a 24‐h continuous infusion of linotroban or placebo. Glomerular filtration rate and effective renal plasma flow were measured. Infusions of cisplatin decreased glomerular filtration rate by 17 ± 25 mL min−1 (P = 0.049 vs. baseline) and effective renal plasma flow by 94 ± 150 mL min−1 (P = 0.049 vs. baseline) in the placebo group. In the linotroban group a decrease in glomerular filtration rate by 11 ± 18 mL min−1 (P = 0.050 vs. baseline) and in effective renal plasma flow by 26 ± 63 mL min−1 (P = 0.2 vs. baseline) was noted. However, no difference was noted between groups in response to treatment. Our findings indicate that linotroban may not be useful for prevention of cisplatin's acute nephrotoxic effects.

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Indication	Highest Phase	Country/Location	Organization	Date
Thrombosis	Phase 2	-	-	-
Thrombosis	Phase 2	AT	-	-

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