Ronald Dotson

Characterization of CGS 8515 as a selective 5-lipoxygenase inhibitor using in vitro and in vivo models

CGS 8515 inhibited 5-hydroxyeicosatetraenoic acid (5-HETE) and leukotriene B4 synthesis in guinea pig leukocytes (IC50 = 0.1 microM). The compound did not appreciably affect cyclooxygenase (sheep seminal vesicles), 12-lipoxygenase (human platelets), 15-lipoxygenase (human leukocytes) and thromboxane synthetase (human platelets) at concentrations up to 100 microM. CGS 8515 inhibited A23187-induced formation of leukotriene products in whole blood (IC50 values of 0.8 and 4 microM, respectively, for human and rat) and in isolated rat lung (IC50 less than 1 microM) in vitro. The selectivity of the compound as a 5-lipoxygenase inhibitor was confirmed in rat whole blood by the 20-70-fold separation of inhibitory effects on the formation of leukotriene from prostaglandin products. Ex vivo and in vivo studies with rats showed that CGS 8515, at an oral dose of 2-50 mg/kg, significantly inhibited A23187-induced production of leukotrienes in whole blood and in the lung. The effect persisted for at least 6 h in the ex vivo whole blood model. CGS 8515, at oral doses as low as 5 mg/kg, significantly suppressed exudate volume and leukocyte migration in the carrageenan-induced pleurisy and sponge models in the rat. Inhibitory effects of the compound on inflammatory responses and leukotriene production in leukocytes and target organs are important parameters suggestive of its therapeutic potential in asthma, psoriasis and inflammatory conditions.

Synthesis and biological activity of phenoxyphenyl oxamic acid derivatives related to L-thyronine.

The synthesis of substituted phenoxyphenyl oxamic acid derivatives related to L-thyronine (L-T3) is described. The in vitro and in vivo cholesterol lowering and cardiovascular effects of these compounds are presented and discussed.

Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 7. pyridinylalkyl-substituted arylsulfonylamino arylalkanoic acids.

Abstract Arylsulfonylamino arylalkanoic acids substituted with a pyridinylalkyl group on the arylalkanoic acid portion of the molecule were synthesized and found to behave as thromboxane receptor antagonists (TxRAs) and thromboxane synthase inhibitors (TxSIs). One of these compounds (11), with a 1,3,5-trisubstituted central aromatic ring was demonstrated to have good functional bioavailability and efficacy as a platelet inhibitor in guinea pigs.

Beneficial effects of combined thromboxane synthase inhibition/receptor blockade with CGS 22652 in a canine model of coronary thrombosis

Various antiplatelet agents were examined for their effectiveness as adjuncts to thrombolytic therapy in a canine model of thrombin-induced coronary thrombosis. Aspirin (5 mg/kg i.v. bolus), CGS 15435A (thromboxane synthase inhibitor (TxSI), 0.1 mg/kg i.v. bolus +0.04 mg/kg per h) and BM 13.505 (thromboxane receptor antagonist (TxRA), 0.5 mg/kg i.v. bolus +0.2 mg/kg per h) administered concurrently with streptokinase (750,000 units/h) were examined for their effects on reperfusion and reocclusion, as were a combination therapy with CGS 15435A + BM 13.505 or the dual TxRA/TxSI inhibitor, CGS 22652 (1 mg/kg i.v. bolus +0.4 mg/kg per h). All dogs received heparin (150 U/kg bolus + 50 U/kg per h) throughout the experimental protocol. Survival analysis at reperfusion indicated that thrombolysis was significantly improved in dogs treated with CGS 15435A, BM 13.505, CGS 15435A+BM 13.505 or CGS 22652 over that of vehicle-treated animals. Both dual inhibitor groups and the BM 13.505 group were significantly different from aspirin. Aspirin-treated dogs were not different from vehicle. Otherwise, all treatments differed from the vehicle-treated group at reocclusion. Time and incidence of reocclusion for CGS 22652 was significantly improved over that of BM 13.505. Residual thrombus weight was significantly reduced in the CGS 22652-treated and BM 13.505 + CGS 15435A-treated animals. These findings demonstrate that streptokinase-induced thrombolysis is accompanied by TxA2/prostaglandin H2 synthesis and platelet activation and suggest a role for platelet activation during reocclusion following clot lysis. These studies also show it is possible to combine the beneficial effects of both a TxRA and TxSI into a single chemical entity, CGS 22652, which, when administered as adjunctive therapy to streptokinase, results in an apparent synergistic antithrombotic effect.

Thia-prostanoid analogs with combined thromboxane receptor antagonist/thromboxane synthase inhibitor activities. Synthesis and pharmacological evaluation

This report describes the incorporation of thia-prostanoid, amino-prostanoid and thromboxane synthase inhibitor features into a new series of thia-prostanoids that combines potent thromboxane receptor antagonist/thromboxane synthase inhibitor activities. Synthesis and biological evaluation is discussed.

OXA-PROSTANOID ANALOGS. IDENTIFICATION OF AN ORALLY EFFECTIVE, DUAL THROMBOXANE RECEPTOR ANTAGONIST/THROMBOXANE SYNTHASE INHIBITOR

Abstract The synthesis and pharmacological evaluation of oxa-prostanoid analogs with dual thromboxane receptor antagonist (TxRA)/thromboxane synthase inhibitor (TxSI) activities are described. One analog 6 with the desirable long lasting oral TxRA/TxSI activity has been identified.

Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 6. 4-substituted 3-pyridinylalkanoic acids.

Abstract (3-Pyridinyl)alkanoic acids substituted at the 4-position with an (arylsulfonamido)alkyl group were synthesized and found to behave as platelet thromboxane receptor antagonists (TxRAs) and thromboxane synthase inhibitors (TxSIs). The compounds behaved as agonists at the vascular receptor for thromboxane A2.