Design, Synthesis and Biological Evaluation of a Novel Series of Potent, Orally Active Adenosine A1 Receptor Antagonists with High Blood-Brain Barrier Permeability.

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 A2A 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 (Ki50.026 nM, A2A/A155400). 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 (n53); after 30 min, plasma conc.533906651 nM, brain conc.536706496 nM; after 60 min, plasma conc.515806348 nM, brain conc.521436434 nM), and a good brain/plasma ratio (1.1160.060 (30 min), 1.3960.172 (60 min)). 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 (Ki56.6 nM, A2A/A15820, BA560.664.9% (32 mg/kg)).