Home
Resources
Publications
Design, Synthesis and Biological Evaluation of a Novel Series of Potent, Orally Active Adenosine A1 Receptor Antagonists With High Blood-Brain Barrier Permeability

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

S Kuroda, F Takamura, Y Tenda, H Itani, Y Tomishima, A Akahane, K Sakane

Chem Pharm Bull (Tokyo). 2001 Aug;49(8):988-98.

PMID: 11515591

Abstract:

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)).

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP202646808	FR194921		202646-80-8	Price

As a specialist in analytical chemical Products, Alfa Chemistry offers consumers a wealth of raw materials and a full range of technologies and services.

QUICK LINKS

HEADQUARTERS

Tel:

Fax:

Email: