Design, Synthesis and Biological Evaluation of a Novel Series of Potent, Orally Active Adenosine A_1 Receptor Antagonists with High Blood-Brain Barrier Permeability

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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 A_1 and A_<2A> receptor binding activites, and in vitro metabolism by rat liver in order to search for orally active compounds. Most of the test compounds were potent adenosine A_1 receptor antagonists with high A_1 selectivity and the A_1 affinity and A_a selectivity of carbonyl derivatives(5-11)was particularly high. In particular, compound 7 was an extremely potent and selective adenosine A_1 antagonist with high A_1 selectivity(Ki=0.026nM, A_<2A>/A_1=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 : 32mg/kg(n=3) ; after 30min, 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 A_1 receptor antagonist with high blood-brain barrier permeability and good bioavailability(Ki=6.6nM, A_<2A>/A_1=820, BA=60.6±4.9%(32ng/kg)).
公益社団法人日本薬学会の論文
2001-08-01

Design, Synthesis and Biological Evaluation of a Novel Series of Potent, Orally Active Adenosine A_1 Receptor Antagonists with High Blood-Brain Barrier Permeability

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