Sujet(s)
Dermatomyosite , Glucocorticoïdes , Hélicase IFIH1 inductrice de l'interféron/immunologie , Pneumopathies interstitielles , Ribonucléosides , Tacrolimus , Autoanticorps/sang , Dermatomyosite/sang , Dermatomyosite/complications , Dermatomyosite/diagnostic , Dermatomyosite/traitement médicamenteux , Surveillance des médicaments/méthodes , Association de médicaments/méthodes , Femelle , Glucocorticoïdes/administration et posologie , Glucocorticoïdes/effets indésirables , Humains , Immunosuppresseurs/administration et posologie , Immunosuppresseurs/effets indésirables , Pneumopathies interstitielles/complications , Pneumopathies interstitielles/diagnostic , Pneumopathies interstitielles/traitement médicamenteux , Pneumopathies interstitielles/physiopathologie , Mâle , Adulte d'âge moyen , Pronostic , Ribonucléosides/administration et posologie , Ribonucléosides/effets indésirables , Indice de gravité de la maladie , Tacrolimus/administration et posologie , Tacrolimus/effets indésirables , Tomodensitométrie/méthodes , Résultat thérapeutiqueRÉSUMÉ
A novel series of 3-(2-substituted-3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridines (5-38) were synthesized and evaluated for their in vitro adenosine A1 and A(2A) receptor binding activities, and in vitro metabolism by rat liver in order to search for orally active compounds. Most of the test compounds were potent adenosine A1 receptor antagonists with high A1 selectivity and the A1 affinity and A1 selectivity of carbonyl derivatives (5-11) was particularly high. In particular, compound 7 was an extremely potent and selective adenosine A1 antagonist with high A1 selectivity (Ki=0.026 nM, A(2A)/A1=5400). In terms of metabolic stability, 2-oxopropyl (5), 2-hydroxypropyl (12), N-methylacetamide (16), 2-(piperidin-1-yl)ethyl (28) and 1-methylpiperidin-4-yl (32, FR194921) were the most stable compounds in this series of analogues. Further in vivo evaluation indicated that compounds 5, 13, 17, 28 and 32 were detected in both plasma and brain after oral administration in rats. In particular, 32 displayed good plasma and brain concentrations (dose: 32 mg/kg (n=3); after 30 min, plasma conc.=3390+/-651nM, brain conc.=3670+/-496nM; after 60min, plasma conc.=1580+/-348nM, brain conc.=2143+/-434nM), and a good brain/plasma ratio (1.11+/-0.060 (30min), 1.39+/-0.172 (60min)). As a result, we could show that 32 is a good candidate for an orally active adenosine A1 receptor antagonist with high blood-brain barrier permeability and good bioavailability (Ki=6.6nM, A(2A)/A1=820, BA=60.6+/-4.9% (32 mg/kg)).
Sujet(s)
Barrière hémato-encéphalique/physiologie , Perméabilité capillaire/physiologie , Évaluation préclinique de médicament/méthodes , Antagonistes des récepteurs purinergiques P1 , Pyridines/synthèse chimique , Pyridines/pharmacocinétique , Administration par voie orale , Animaux , Barrière hémato-encéphalique/effets des médicaments et des substances chimiques , Encéphale/métabolisme , Cellules CHO , Cellules COS , Perméabilité capillaire/effets des médicaments et des substances chimiques , Cricetinae , Humains , Foie/métabolisme , Mâle , Pyridines/métabolisme , Rats , Rat Sprague-Dawley , Récepteurs purinergiques P1/métabolismeRÉSUMÉ
The present study examined the inhibitory effects of N-hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine (HET0016) on the renal metabolism of arachidonic acid by cytochrome P450 (CYP) enzymes. HET0016 exhibited a high degree of selectivity in inhibiting the formation of 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) in rat renal microsomes. The IC(50) value averaged 35+/-4 nM, whereas the IC(50) value for inhibition of the formation of epoxyeicosatrienoic acids by HET0016 averaged 2800+/-300 nM. In human renal microsomes, HET0016 potently inhibited the formation of 20-HETE with an IC(50) value of 8.9+/-2.7 nM. Higher concentrations of HET0016 also inhibited the CYP2C9, CYP2D6 and CYP3A4-catalysed substrates oxidation with IC(50) values of 3300, 83,900 and 71,000 nM. The IC(50) value for HET0016 on cyclo-oxygenase activity was 2300 nM. These results indicate that HET0016 is a potent and selective inhibitor of CYP enzymes responsible for the formation of 20-HETE in man and rat.