Effect of BAY U 3405, a new thromboxane antagonist, on sudden death in rabbits.

We studied the effects of BAY U 3405 in experimental models of arachidonic acid- and collagen-induced sudden death. BAY U 3405 was effective in dose-dependently inhibiting death from both arachidonic acid and collagen at doses of 1, 3 and 10 mg/kg orally. The survival rate, usually amounting to less than 10% in vehicle-treated animals, was dramatically increased to 100% at the highest dose. The data obtained emphasize the role of thromboxane A2 as a mediator in this model, and the potential usefulness of BAY U 3405 for thromboembolic disorders.

Characterization of Bay U 3405, a novel thromboxane A2/endoperoxide receptor antagonist.

The thromboxane A2-receptor antagonistic properties of Bay U 3405 [(3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbaz o-lepropanoic acid] have been evaluated in various pharmacologic models. Bay U 3405 specifically inhibits platelet aggregation induced by U 46619, collagen, platelet-activating factor, and the second wave of ADP (IC50 0.5, 0.07, 0.3, 0.19 microM) in human plasma. The plasma phase of ADP-induced aggregation is not affected. U 46619-induced platelet aggregation is competitively antagonized (pA2 = 6.3). In humans, ex vivo platelet aggregation is inhibited after oral application of 2 or 50 mg Bay U 3405. Bay U 3405 also specifically and competitively antagonizes U 46619-induced contractions of rabbit aortic rings (pA2 = 7.4). In vivo, Bay U 3405 protects rabbits dose dependently from arachidonic acid or collagen-induced thromboembolism (ED50 1-3 mg/kg p.o). Chronic administration of Bay U 3405 to stroke-prone spontaneously hypertensive rats reduces stroke-related mortality and diminishes the occurrence of cerebral hemorrhages. From these results, we conclude that Bay U 3405 is an orally active, selective, and competitive thromboxane A2-receptor antagonist that may be beneficial in the treatment of cardiovascular or cerebrovascular diseases.

Synthesis and absolute configuration of the new thromboxane antagonist (3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbazolepropan oic acid and comparison with its enantiomer.

The synthesis of (3R)-3-(4-Fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9- carbazolepropanoic acid (Bay u 3405), a new, enantiomerically pure antagonist of thromboxane A2, is described. The determination of the absolute configuration of Bay u 3405 was performed by an X-ray analysis of compound 7 ([3((2S)-acetylamido)-3-phenylpropionamido]-1,2,3,4- tetrahydro-carbazol). Bay u 3405 is in vitro 1 to 2 orders of magnitude more active than its (-)-enantiomer Bay u 3406.

Action of the novel selective thromboxane antagonist (3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbazolepropan oic acid on vascular smooth muscle preparations.

The action of the thromboxane A2-receptor-antagonist (3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbazo lepropanoic acid (Bay u 3405) on vascular smooth muscle preparations was investigated in vitro. In rabbit aortic rings Bay u 3405 is a potent inhibitor of vasoconstriction produced by thromboxane A2 (TXA2)/PG endoperoxides generated by stimulated human platelets (EC50 1.3 x 10(-6) mol/l), (+/-)-cTA2 (Carbocyclic thromboxane A2 [2 beta(Z),3 alpha-(1E,3R*)-3- (3-hydroxy(1-octenyl)-bicyclo[3.1.1]hept-2-yl-5-heptenoic acid]) (EC50 3.3 x 10(-7) mol/l) and U 46619 (EC50 3.8 x 10(-7) mol/l). In pig circumflex coronary arteries Bay u 3405 was 150 times more potent (EC50 2.6 x 10(-9) mol/l) than in rabbit aorta. In rabbit and rat aorta the concentration-response curves for U 46619 were shifted to the right in a parallel manner and the maximum responses were not suppressed. The Schild-plot yielded a straight line with a slope of 1.14 (rabbit) or 1.29 (rat) and pA2 values of 7.43 and 8.59, respectively. The vasoconstrictive action of other agonists such as KCl, serotonin, histamine, epinephrine, norepinephrine, acetylcholine and angiotensin were not affected. In human platelets inhibition of the TXA2-synthase was seen only at concentrations of Bay u 3405 of 2.4 x 10(-5) mol/l and above. From these findings it is concluded that Bay u 3405 is a potent, competitive TXA2/endoperoxide receptor antagonist in vascular smooth muscle.

Inhibition of platelet aggregation in vitro and ex vivo by the new thromboxane antagonist (3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9- carbazolepropanoic acid.

(3R)-3-(4-Fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbazo lepropanoic acid (Bay u 3405) was tested for inhibition of platelet aggregation in vitro (human platelet rich plasma) and ex vivo (rat). Aggregation induced by collagen, arachidonic acid, thrombin, adenosine diphosphate (ADP, biphasic response), epinephrine and U 46619 was inhibited at minimum effective concentrations of 0.01 to 0.1 micrograms/ml in vitro. Following oral administration to rats the ED50 for the dose-dependent inhibition was 36 micrograms/kg. At a dose of 100 micrograms/kg p.o. significant inhibition was obtained up to 16 h. Bay u 3405 is considered a potential drug for treatment of some cardiovascular disorders.

Reduction of in vivo coronary artery thrombosis by the novel thromboxane antagonist (3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9- carbazolepropanoic acid.

The effects of thromboxane (Tx)A2 antagonism were examined in a canine model of platelet-dependent coronary occlusion. The novel TxA2 antagonist (3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbazo lepropanoic acid (Bay u 3405) was studied to ensure that antithrombotic effects seen in vivo were platelet-mediated and did not reflect unspecific compound effects. Bay u 3405 (1, 3, 10 and 30 mg/kg i.v.) inhibited in vivo platelet aggregation and increased the time to thrombotic vascular occlusion by 2.8 h (p less than 0.05) after 30 mg/kg were given. A dose-dependent reduction of intravascular occlusive thrombus growth occurred: thrombus wet weight decreased from 66 +/- 6 mg in vehicle controls to 42 +/- 6 mg, 25 +/- 5 mg, 18 +/- 3 mg and 6 +/- 2 mg after administration of 1, 3, 10 and 30 mg Bay u 3405 i.v., respectively. Electrocardiographic signs for developing myocardial ischemia were largely prevented by the compound. Collagen-induced platelet aggregation ex vivo was inhibited by over 60% in drug-treated animals. The observed delay of thrombotic coronary occlusion reflected an inhibition of platelet aggregation and protection from coronary vasoconstriction at the site of thrombus formation, most likely mediated through blockade of TxA2 receptors.

Tick repellents II: N-substituted azacyclopentanones and azacyclopentenones.

Several N-substituted azacyclopentanones and azacyclopentenones were synthesized and evaluated as repellents for the brown dog tick Rhipicephalus sanguineus. Several of these compounds were more effective in our test system than were the standard repellents, N,N-diethyl-m-toluamide and butopyranoxyl.

Toxicity of 1,4-dihexylpiperazine.

Attempts to synthesize the insect repellent, N,N'-dihexyl-N-carbomethoxyethylenediamine, led to an impurity which exhibited strong toxicity in the rabbit eye irritation test. Isolation of the impurity led to its identification at 1,4-dihexylpiperazine.