Design, synthesis and biological evaluation of a novel series of potent, orally active adenosine A(1) receptor antagonists with high blood-brain barrier permeability

A novel series of 3-(2-substituted-3-oxo-2,3-dihydropyridazin-6-yl)-2-pheny lpyrazolo [1,5-a]pyridines (5-38) were synthesized and evaluated for their in vitro adenosine A(1) and A(2A) receptor binding activities, and in vitro metabolism by rat liver in order to search for orally active compounds. Mo st of the test compound,, were potent adenosine A(1) receptor antagonists w ith high A(1) selectivity and the A(1) affinity and A(1) selectivity of car bonyl derivatives (5-11) was particularly high. In particular, compound 7 w as an extremely potent and selective adenosine A(1) antagonist with high A( 1) selectivity (Ki=0.026 nM, A(2A)/A(1) =5400). In terms of metabolic stabi lity. 2-oxopropyl (5), 2-hydroxypropyl (12), N-methylacetamide (16), 2-(pip eridin-1-yl)ethyl (28) and 1-methylpiperidin-4-yl (32, FR194921) were the m ost stable compounds in this series of analogues. Further in vivo evaluatio n indicated that compounds 5, 13, 17, 28 and 32 were detected in both plasm a and brain after oral administration in rats. In particular, 32 displayed good plasma and brain concentrations (dose: 32mg/kg (n=3); after 30min, pla sma conc =3390 +/- 651 nM, brain conc.=3670 +/- 496nM; after 60 min, plasma conc.= 1580 +/- 348 nM, brain cone. =2143 +/- 434 nM), and a good brain/pl asma ratio (1.11 +/-0.060 (30 min). 1.39 +/- 172 (60 min)). As a result, we could show, that 32 is a good candidate for an orally active adenosine A, receptor antagonist with high blood-brain barrier permeability and good bio avail ability (Ki=6.6nM, A(2A)/A(1)=820, BA=60.6 +/-4.9% (32mg/kg)).