isbogrel and ridogrel

Synthesis and pharmacological evaluation of novel indazole derivatives are described. These compounds were found to exhibit both thromboxane A2 (TXA2) synthetase-inhibitory and bronchodilatory activities. This observation supports the idea that the partial structure of the 3-pyridyl and phenyl groups with a methylene insertion is an important component for well-balanced activities.

Topics: Administration, Oral; Aminophylline; Animals; Benzofurans; Bronchodilator Agents; Fatty Acids, Monounsaturated; Guinea Pigs; Histamine Antagonists; In Vitro Techniques; Indazoles; Male; Methacrylates; Pentanoic Acids; Pyridines; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Thromboxane-A Synthase; Trachea

R 68070 and CV-4151 are two compounds possessing both thromboxane synthetase inhibitory activity and thromboxane receptor antagonist properties. 2-Heteroaryl 2-substituted phenylketone derivatives with a partial structural similarity to R 68070 and CV-4151, i.e. possessing a phenyl and a heteroaryl moiety, have been prepared and found to have antiplatelet activity. The compound 2-thienyl 2'-hydroxyphenyl ketone (4) was shown to completely inhibit platelet aggregation induced by arachidonic acid at a concentration of 5.0 microM. Structure-activity analysis indicated that the presence of a ketone group is an important requirement for this inhibitory activity. An o-hydroxyl substitution on the phenyl ring, and a 2-thienyl of heteroaryl ring might increase inhibitory activity.

Topics: Animals; Fatty Acids, Monounsaturated; Fibrinolytic Agents; Magnetic Resonance Spectroscopy; Mass Spectrometry; Pentanoic Acids; Platelet Aggregation Inhibitors; Pyridines; Rabbits; Structure-Activity Relationship; Thromboxane B2; Thromboxane-A Synthase

1. The present study has compared the relative anti-aggregatory effect of various compounds which interfere with thromboxane (Tx) A2-dependent aggregation of human platelets in whole blood in vitro. These included the cyclo-oxygenase inhibitor aspirin, the TxA2 synthase inhibitor dazoxiben, the TxA2 (TP-) receptor blocking drug GR32191 and two compounds, R.68070 ((E)-5-[[[(3-pyridinyl) [3-(trifluoromethyl)phenyl]-methylen] amino]oxy] pentanoic acid) and CV-4151 [E)-7-phenyl-7-(3-pyridyl)-6-heptenoic acid), which possess both TP-receptor blocking and TxA2 synthase inhibitory activities in the same molecule. 2. GR32191, R.68070 and CV-4151 all antagonized aggregation to the TxA2 mimetic U-46619, with pA2 values of approximately 8.2, 5.4 and 4.8 respectively. This effect was specific, platelet aggregation induced by adenosine 5'-diphosphate (ADP) being unaffected by concentrations up to 10, 1000 and 300 microM respectively. In contrast, neither aspirin nor dazoxiben exhibited any measurable TP-receptor blocking activity. 3. The rank order of potency (pIC50) for inhibition of TxA2 formation in serum was R.68070 (7.4) greater than CV-4151 (6.9) greater than dazoxiben (5.7) greater than aspirin (5.3). In addition, all four drugs abolished collagen-induced platelet TxA2 formation. In contrast, GR32191 produced no consistent inhibition of TxA2 formation in either system up to concentrations of 10-30 microM. 4. The specificity of R.68070, CV-4151 and dazoxiben for TxA2 synthase was indicated by their ability to increase serum levels of prostaglandin E2 (PGE2) and PGD2 in parallel with decreases in TxA2 formation. This profile was not observed with aspirin or GR32191. However, high concentrations of R.68070 (100,microM) and CV-4151 (1000 microM) necessary for maximum TP-receptor blocking activity, produced substantially smaller increases in PGE2 and PGD2, consistent with an aspirin-like effect of these compounds upon cyclo-oxygenase. With dazoxiben (1000 microM), PGE2 and PGD2 levels remained elevated. 5. Aspirin inhibited collagen-induced platelet aggregation, the effect correlating with inhibition of TxA2 formation. Dazoxiben, whilst also achieving maximal inhibition of TxA2 formation, produced significantly less inhibition of aggregation than aspirin. In contrast, GR32191 (0.1-1O microM), at concentrations specific for TP-receptor blockade, produced a significantly greater antagonism of collagen-induced platelet aggregation than aspirin. This additional effect o

Topics: Aspirin; Biphenyl Compounds; Drug Interactions; Fatty Acids, Monounsaturated; Heptanoic Acids; Humans; Imidazoles; In Vitro Techniques; Male; Pentanoic Acids; Platelet Aggregation; Platelet Aggregation Inhibitors; Pyridines; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane-A Synthase

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Biphenyl Compounds; Collagen; Fatty Acids, Monounsaturated; Heptanoic Acids; Humans; In Vitro Techniques; Pentanoic Acids; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Pyridines; Thromboxane-A Synthase; Valerates