Synthesis and biological evaluation of 3,4-diaryloxazolones: A new class of orally active cyclooxygenase-2 inhibitors.

A series of 3,4-diaryloxazolones were prepared and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2). Extensive structure-activity relationship work was carried out within this series, and a number of potent and selective COX-2 inhibitors were identified. The replacement of the methyl sulfone group on the 4-phenyl ring by a sulfonamide moiety resulted in compounds with superior in vivo antiinflammatory properties. In the sulfonamide series, the introduction of a methyl group at the 5-position of the oxazolone ring gave rise to very COX-2-selective compounds but with decreased in vivo activity. Selected 3,4-diaryloxazolones exhibited excellent activities in experimental models of arthritis and hyperalgesia. The in vivo activity of these compounds was confirmed with the evaluation of their antipyretic effectiveness and their ability to inhibit migration of proinflammatory cells. As expected from their COX-2 selectivity, most of the active compounds lacked gastrointestinal toxicity in vivo in rats after a 4-day treatment of 100 mg/kg/day. Within this novel series, sulfonamides 9-11 have been selected for further preclinical evaluation.

Studies on the cardiac actions of flosequinan in vitro.

1. We have investigated the in vitro cardiac actions of flosequinan and of its major metabolite in man, BTS 53554. 2. Positive inotropic activity was seen with flosequinan in guinea-pig isolated ventricles, the threshold concentration for effect being less than 1 x 10(-5) M. BTS 53554 was approximately half as potent as the parent compound. 3. In guinea-pig working whole hearts flosequinan increased left ventricular dp/dtmax, indicating a positive inotropic action. This effect was accompanied by increases in heart rate, cardiac output and stroke volume. 4. The virtual complete inhibition of inotropic responses to flosequinan and BTS 53554 by carbachol suggests that these responses are adenosine 3':5'-cyclic monophosphate (cyclic AMP)-mediated. 5. Flosequinan was shown to increase calcium inward current in guinea-pig ventricle, an action consistent with a cyclic AMP involvement in the response. 6. The inotropic activity of flosequinan was not potentiated by the selective phosphodiesterase (PDE) III inhibitor SK&F 94120, a result which indicates that flosequinan does not increase cyclic AMP concentrations via stimulation of adenylate cyclase. 7. Flosequinan inotropic responses were potentiated by rolipram, a selective PDE IV inhibitor, a result consistent with flosequinan being itself a PDE III inhibitor. 8. Biochemical studies with purified enzymes confirmed that flosequinan and BTS 53554 are relatively selective inhibitors of PDE III. 9. A comparison of pharmacological and biochemical data for both flosequinan and BTS 53554 indicates that their PDE III inhibitory potency is sufficient to account for their inotropic activity.

Investigation into the role of phosphodiesterase IV in bronchorelaxation, including studies with human bronchus.

1. We have investigated the role of cyclic nucleotide phosphodiesterase IV (PDE IV) in the relaxation of human bronchus and guinea-pig trachea in vitro and in guinea-pigs in vivo. 2. Functional studies showed that the selective PDE IV inhibitors, rolipram and denbufylline, relaxed human and guinea-pig preparations in vitro. 3. Two clinically used xanthine non-selective PDE inhibitors, theophylline and pentoxifylline, were also effective in these preparations, but were much less potent than the selective agents used. 4. The rank order of potency for the four PDE inhibitors in both species was similar. 5. Biochemical studies indicated that PDE IV was the major PDE isoform present in the human bronchial tissue. PDEs I, II and V were also identified. 6. Theophylline and pentoxifylline were, as expected, non-selective inhibitors of the human enzymes, but there was a good correlation between PDE IV inhibitory and bronchorelaxation potencies, suggesting that PDE IV inhibition is important for the clinical bronchodilator activities of the two xanthine compounds. 7. We have confirmed the ability of selective PDE IV inhibitors to cause bronchodilatation in guinea-pigs in vivo. 8. We conclude that our study has provided further evidence that selective PDE IV inhibitors could act as bronchodilators in the clinic.

Cardiotoxicity of histamine and the possible role of histamine in the arrhythmogenesis produced by certain antihistamines.

Since 1990 it has repeatedly been reported that some histamine H1 receptor antagonists (e.g. terfenadine and astemizole) are able to produce ventricular arrhythmias (e.g. torsade de pointes) when they are given at dosages above the therapeutic range and/or administered together with cytochrome P-450 3A4 inhibitors, such as ketoconazole or erythromycin. Although the mechanism by which these arrhythmias are produced remains unclear, the recently reported ability of these drugs to block outward K+ currents has been suggested as the cause of their arrhythmogenic effects. Alternatively, we have observed that some H1 antihistamines, including terfenadine and astemizole, are able to release histamine from guinea-pig cardiac mast cells. Thus, we have proposed that the liberated histamine, acting through an H2 receptor-stimulating mechanism, can prolong the action potential duration and hence induce arrhythmogenic effects. This paper describes experimental observations supporting the hypothesis that some H1 antihistamines can induce severe cardiac arrhythmias via the local release of histamine.

Inhibition of lipopolysaccharide-induced bowel erythrocyte extravasation in rats, and of mesenteric hypoperfusion in dogs, by phosphodiesterase inhibitors.

Sepsis is intricately associated with mesenteric ischemia. The remote complications of mesenteric ischemia are essentially those of sepsis, whether as a cause or as a consequence. Experimental endotoxic shock induces bowel hypoperfusion, erythrocyte extravasation and intestinal necrosis. The effects of pentoxifylline, rolipram and denbufylline, three phosphodiesterase inhibitors, were studied on endotoxin-induced bowel erythrocyte extravasation and intestinal and renal hypoperfusion, in conscious rats and anaesthetized dogs, respectively. Two hours after lipopolysaccharide i.v. injection in rats, erythrocyte extravasation was evident throughout the intestinal musculature and mucosa, apparently without affecting lungs, heart, kidneys, liver or pancreas. Pretreatment with the non-selective phosphodiesterase inhibitor, pentoxifylline, or selective phosphodiesterase IV inhibitors such as denbufylline or rolipram reduced intestinal haemoconcentration. In the anaesthetized dog, pentoxifylline and denbufylline both inhibited the E. coli lipopolysaccharide-induced mesenteric blood flow fall, without affecting renal blood flow or cardiac index. In conclusion, phosphodiesterase inhibitors protected from intestinal damage and bowel hypoperfusion after lipopolysaccharide challenge. This action may thus play a role in the protective effects against endotoxin-induced lethal toxicity previously described for phosphodiesterase inhibitors.

Cardiovascular safety profile of almotriptan, a new indolic derivative for the treatment of migraine.

Almotriptan is a new 5-HT(1B/1D) receptor agonist effective for treating acute migraine attacks with or without aura. As 3-5% of patients treated with sumatriptan experience chest symptoms thought to be of cardiac origin, we investigated the cardiovascular safety profile of almotriptan in comparison with that of sumatriptan in six animal models. Almotriptan did not modify blood pressure or heart rate in conscious telemetered normotensive Wistar rats (p.o.), in anaesthetised beagle dogs (i.v.), or in conscious beagle dogs (i.v.), and only produced transient increases when administered (s.c.) to telemetered cynomolgus monkeys. Almotriptan did not consistently affect the duration of the electrocardiogram (ECG) intervals in anaesthetised beagle dogs even when the drug was administered into the coronary artery, nor was ECG morphology altered in telemetered cynomolgus monkeys. In contrast, sumatriptan i.v. consistently increased mean blood pressure and heart rate in conscious beagle dogs. Finally, almotriptan did not modify coronary blood flow at a dose of up to 0.3 mg/kg i.v. in conscious beagle dogs. Thus, almotriptan has a favourable cardiovascular safety profile.

Anticholinergic effects of desloratadine, the major metabolite of loratadine, in rabbit and guinea-pig iris smooth muscle.

Allergic conjunctivitis is the most common ocular allergic disease. Although very symptomatic it does not endanger vision, and topical antihistamines or chromones are the first choice treatment in clinical practice. Recently, equivalent nanomolar affinities for histamine H and muscarinic M 1 and M3 cloned human receptors have been reported for desloratadine, the active metabolite of loratadine, a widely prescribed antihistamine. This property might enhance its utility in the treatment of asthma, but could induce adverse anticholinergic effects after topical administration. In the present study, we compare the anticholinergic activity of desloratadine with other known muscarinic antagonists and antihistamines on rabbit and guinea-pig iris smooth muscle. Desloratadine was found to be a competitive antagonist (pA2 = 6.67+/-0.09) of carbachol-induced contractions in isolated rabbit iris smooth muscle. Atropine (pA2 = 9.44+/-0.02) and NPC-14695 (pA2 = 9.18+/-0.03) also behaved as competitive antagonists, whereas tiotropium bromide (pD'2 = 9.06+/-0.02) exhibited a non-competitive behaviour in this tissue. Carebastine (pA2 = 5.64+/-0.04) and fexofenadine (pA2 < 4.0) were also studied. After topical administration on the guinea-pig eye conjunctiva, desloratadine produced a potent (ED50 = 2.3 mg/ml) and long lasting mydriasis (> 120 min at the ED50) in conscious animals. Fexofenadine and carebastine were inactive even at the highest concentration tested (10 mg/ml). Atropine (ED50 = 30 microg/ml) and tiotropium bromide (ED50 = 10 microg/ml) were much more potent than desloratadine or pirenzepine (ED50 = 3 mg/ml) in this model. The competitive muscarinic antagonism of desloratadine in vitro, and its potency and duration of action in vivo, suggest that topical treatment of allergic conjunctivitis and rhinitis with desloratadine could produce undesirable peripheral anticholinergic side effects such as mydriasis and xerostomia.

Synthesis and pharmacological evaluation of 2, 3-dihydro-3-oxo-4H-thieno[3,4-e][1,2,4]thiadiazine 1,1-dioxides as voltage-dependent calcium channel blockers.

The synthesis of a novel series of 2,3-dihydro-3-oxo-4H-thieno[3, 4-e][1,2,4]thiadiazine 1,1-dioxides and their pharmacological evaluation as drugs with effects on the rat cardiovascular system are described. The compounds under study were synthesized via Curtius rearrangement of appropriate sulfamoylacylazides which, in turn, were prepared from known starting materials. In isolated rat portal vein, these thienothiadiazines, like verapamil and diazoxide, inhibited the spontaneous motility produced by KCl (20 mM). In addition, the new compounds, like verapamil and unlike diazoxide, also exhibited inhibitory effects in the same preparation when the cell membrane was depolarized by an increased extracellular KCl concentration (80 mM) and, consequently, the membrane potential approached a level close to the K(+) equilibrium potential. Further characterization of this inhibitory activity led to the identification of a selective inhibitory effect of the new compounds on KCl (80 mM)-induced 45Ca(2+) uptake in the same vascular tissue. When tested in vivo (anaesthetized normotensive rats), acute administration of verapamil, diazoxide and some of the most in vitro potent compounds in 45Ca(2+) uptake experiments produced a gradual, dose-dependent and sustained decrease in diastolic arterial blood pressure, devoid of cardiac effects. These results suggest that, like verapamil, the cardiovascular effects produced by the new thienothiadiazines seem to be due, at least in part, to a blockade of transmembrane voltage-dependent calcium channels present in vascular smooth muscle cells and not to an activation of ATP-sensitive K(+) channels. Compounds 5b, 5e and 5i have been selected for further studies as antihypertensive agents.

Cardiovascular effects of LAS 30538, a new vascular selective Ca(2+)-channel blocker.

A new compound, 1-[2-(2,6-dimethylphenoxy)ethyl]-alpha,alpha-bis-(p-fluorphenyl)-4 -piperidine methanol (LAS 30538), was found to have potent vasodilator effects. Its vasorelaxant activity was demonstrated in rat perfused hindlimbs contracted with 80 mM K+, having an IC50 value of 40 nM. In conscious spontaneously hypertensive rats, LAS 30538 administered orally, caused dose-dependent sustained falls in systolic blood pressure with an ED30 value of 11 mg kg-1. In pithed rats, LAS 30538, strongly inhibited vasoconstriction induced by the alpha 2-adrenoceptor agonist B-HT 933 and the calcium agonist compound Bay K8644 with ED50 values of 4 mg kg-1 p.o. and 1.3 mg kg-1 i.v., respectively. Results from electrophysiological studies carried out using guinea-pig papillary muscles partially depolarized by 22 mM K+ are consistent with LAS 30538 acting as a Ca(2+)-channel blocker. When compared with verapamil, in guinea-pig and rabbit isolated heart preparations, LAS 30538 caused less cardiodepression and bradycardia. The results suggest that LAS 30538 may have some advantages over other Ca(2+)-channel blockers such as verapamil in causing less myocardial depression for a given level of vasodilatation.

Dioxides of bicyclic thiadiazines: a new family of smooth muscle relaxants.

The synthesis of dioxides of bicyclic thiadiazine related to diazoxide has been achieved. In a preliminary test, some of these compounds show smooth muscle relaxation similar to that obtained with the reference standard diazoxide.

[Chronic granulomatous disease: clinical and functional studies in six cases (author's transl)]. / Enfermedad granulomatosa crónica. Evolución clínica y estudios funcionales en seis casos.

Six cases of chronic granulomatous disese (CGD), three of which correspond to the X-linked genetic form and the three other to the autosomic recessive type are reported. The fact of half of the patients being females is relevant as only 24 are cited by Klebanoff and Clark in their revision in 1978. X-linked CGD: The three patients, two of them brothers, presented their first manifestations in the first year of life; in one of the BCG given at one week of life resulted in adenitis of protracted course with calcificaton. The clinical course has been very severe in two of them. At the present time the patients are 15, 11 and 9 years old. Functional studies have shown very low values in NBT tests, O2 consumption, iodination and bactericidal activity in all three. Intermediate values in the mothers and normal values in the fathers were found. Autosomal CGD: Of our three patients, two were sisters. The first manifestations appeared during the first thrimester of life. The eldest had hepatic and pulmonary granulomata at three years old. At five years, she presented an intestinal obstruction syndrome with gastric antral, duodenal and ileal stenosis caused by intramural granulomata and inflammation; she died of pneumonia shortly after. Her sister had dermatitis, hepatic abscess, pneumonia, adenitis and osteomyuelitis of the ribs; she died at six years old after a bronchopneumonia. Last patient had a sister who died at two years old affected probably gy CGD. At present our patient is 17 months old and so far had recurrent otitis, adenitis, a pneumonia and, recently, hepatic granulomata have been found. Fonctional studies in the two sisters showed similar alterations as those of the three boys. In this patient an alteration of chemotaxis of cellular origen was found as well.

Pharmacological profile of LAS 31180, a new inotropic/vasodilator quinolone derivative.

LAS 31180 (3-methylsulphonylamino-1-methyl-4(1H)-quinolone, CAS 137338-43-3) was found to have positive inotropic and vasodilator properties through its inhibitory action on type 3 phosphodiesterase. The inotropic effects of LAS 31180 were demonstrated in vitro both in isolated guinea-pig ventricular strips (EC50 of 1.2 mumol/l) and in isolated guinea-pig working hearts. In conscious chronically instrumented Beagle dogs, LAS 31180 administered either by intravenous or oral route, showed a dose-dependent, long-lasting positive inotropic effect with minimal effects on heart rate. In hypertensive Beagle dogs LAS 31180 elicited a potent and long-lasting fall in blood pressure.

Arylimino-1,2,4-thiadiazolidinones: a new family of potassium channel openers.

A series of arylimino-1,2,4-thiadiazolidines were prepared using an efficient synthesis starting from thiadiazolopyridinium chlorides. All the compounds showed smooth muscular relaxant properties in rat portal veins. The different behaviour under highly depolarized conditions and the reduction of the biological effect by glyburide suggests that the arylimino-1,2,4-thiadiazolidin-3-ones may act, at least in part, via K+-induced hyperpolarization of vascular smooth cells.

Synthesis and potential muscarinic receptor binding and antioxidant properties of 3-(thiadiazolyl)pyridine 1-oxide compounds.

The synthesis of two different series of 3-(thiadiazolyl)pyridine 1-oxide containing 1,2,5- and 1,2,4-thiadiazole moiety respectively is described. The potential muscarinic receptor binding together with the antioxidant properties of the new compounds were evaluated.