Macitentan, also called Actelion-1 or -6-(2-(5-bromopyrimidin-2-yloxy)ethoxy)-pyrimidin-4-yl]-NЈ-propylaminosulfonamide], is a new dual ET A / ET B endothelin (ET) receptor antagonist designed for tissue targeting. Selection of macitentan was based on inhibitory potency on both ET receptors and optimization of physicochemical properties to achieve high affinity for lipophilic milieu. In vivo, macitentan is metabolized into a major and pharmacologically active metabolite, ACT-132577. Macitentan and its metabolite antagonized the specific binding of ET-1 on membranes of cells overexpressing ET A and ET B receptors and blunted ET-1-induced calcium mobilization in various natural cell lines, with inhibitory constants within the nanomolar range. In functional assays, macitentan and ACT-132577 inhibited ET-1-induced contractions in isolated endothelium-denuded rat aorta (ET A receptors) and sarafotoxin S6c-induced contractions in isolated rat trachea (ET B receptors). In rats with pulmonary hypertension, macitentan prevented both the increase of pulmonary pressure and the right ventricle hypertrophy, and it markedly improved survival. In diabetic rats, chronic administration of macitentan decreased blood pressure and proteinuria and prevented end-organ damage (renal vascular hypertrophy and structural injury). In conclusion, macitentan, by its tissuetargeting properties and dual antagonism of ET receptors, protects against end-organ damage in diabetes and improves survival in pulmonary hypertensive rats. This profile makes macitentan a new agent to treat cardiovascular disorders associated with chronic tissue ET system activation.
ABSTRACT:The elimination process of the endothelin receptor antagonist bosentan (Tracleer) in humans is entirely dependent on metabolism mediated by two cytochrome P450 (P450) enzymes, i.e., CYP3A4 and CYP2C9. Most interactions with concomitantly administered drugs can be rationalized in terms of inhibition of these P450 enzymes. The increased bosentan concentrations observed in the presence of cyclosporin A, rifampicin, or sildenafil, however, are incompatible with this paradigm and prompted the search for alternative mechanisms governing these interactions. In the present article, we identify bosentan and its active plasma The phosphodiesterase-5 inhibitor sildenafil was also shown to interfere with OATP-mediated transport, however, at concentrations above those achieved in therapeutic use. Therefore, inhibition of bosentan hepatic uptake may represent an alternative/complementary mechanism to rationalize some of the pharmacokinetic interactions seen in therapeutic use. A similar picture has been drawn for drugs like pitavastatin and fexofenadine, drugs that are mainly excreted in unchanged form. Bosentan elimination, in contrast, is entirely dependent on metabolism. Therefore, the described interactions with rifampicin, cyclosporin A, and, to a lesser extent, sildenafil represent evidence that inhibition of hepatic uptake may become the rate-limiting step in the overall elimination process even for drugs whose elimination is entirely dependent on metabolism.Bosentan (Tracleer) is a dual endothelin receptor antagonist (Clozel et al., 1994;Neidhart et al., 1996) approved as the first oral treatment for pulmonary arterial hypertension (PAH) (Rubin et al., 2002). Its pharmacokinetic profile in humans is characterized by a low systemic plasma clearance of 17 l/h, a volume of distribution of about 30 l, and an oral bioavailability of about 50% (Dingemanse and van . At the maintenance dose of 125 mg b.i.d., bosentan trough concentrations decrease during the first days of treatment as a result of autoinduction of metabolizing enzymes, leading to an about 40% lower exposure at steady state. Bosentan is metabolized in the liver (Fig. 1), mediated to a similar extent by CYP2C9 and CYP3A4, followed by subsequent biliary excretion.Hydroxylation at the t-butyl group by CYP2C9 and CYP3A4 yields metabolite Ro 48-5033, a metabolite that retains pharmacological activity and is present in human plasma at levels of about 10% compared with parent bosentan. Ro 47-8634 is formed by oxidative demethylation of the guaiacol ether, catalyzed by CYP3A4, to the corresponding phenol, whereas metabolite Ro 64-1056 is formed as a minor product from both primary metabolites. Renal clearance of bosentan is negligible (Hopfgartner et al., 1996;Weber et al., 1999b). Based on preclinical data, the first-pass effect of bosentan is small. Bosentan is neither a substrate nor an inhibitor of the intestinal efflux pump MDR1 (P-glycoprotein, ABCB1) (Weber et al., 1999a;Treiber et al., 2004).Most of the pharmacokinetic drug-drug interactions observed w...
Sphingosine-1-phosphate (S1P) is a widespread lysophospholipid which displays a wealth of biological effects. Extracellular S1P conveys its activity through five specific G-protein coupled receptors numbered S1P(1) through S1P(5). Agonists of the S1P(1) receptor block the egress of T-lymphocytes from thymus and lymphoid organs and hold promise for the oral treatment of autoimmune disorders. Here, we report on the discovery and detailed structure-activity relationships of a novel class of S1P(1) receptor agonists based on the 2-imino-thiazolidin-4-one scaffold. Compound 8bo (ACT-128800) emerged from this series and is a potent, selective, and orally active S1P(1) receptor agonist selected for clinical development. In the rat, maximal reduction of circulating lymphocytes was reached at a dose of 3 mg/kg. The duration of lymphocyte sequestration was dose dependent. At a dose of 100 mg/kg, the effect on lymphocyte counts was fully reversible within less than 36 h. Pharmacokinetic investigation of 8bo in beagle dogs suggests that the compound is suitable for once daily dosing in humans.
Direct evidence for the involvement of thiophene S-oxide as a key primary reactive intermediate in the metabolism of thiophene (1) in rats was obtained from the isolation of two diastereoisomeric thiophene S-oxide dimers, 4a and 4b, both in vitro (oxidation of thiophene with rat liver microsomes) and in vivo (isolation of 4a from rat urine). The structure of these dimers was established after an original preparation of identical samples by oxidation of thiophene with H2O2 and CF3COOH. In fact, the H2O2/CF3COOH system appeared to be the best oxidizing agent for the selective transformation of thiophene to its S-oxide. The complete determination of the structures of 4a and 4b was carried out for the first time by X-ray diffraction for the former and by a sequence of chemical reactions for the latter. The reported results indicate two fates for thiophene S-oxide in vivo: (i) its dimerization via a Diels−Alder reaction and (ii) its reaction with nucleophiles such as glutathione leading eventually to mercapturates. These results together with recent literature data on thiophene derivatives suggest that thiophene S-oxides, a class of reactive intermediates whose chemistry is still not well-known, could play a central role in the metabolism and toxic effects of thiophenes in mammals. This situation would be different from that observed in the metabolism of other aromatic compounds, such as benzene or furan, in which arene oxides are predominant intermediates.
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