Discovery of FR166124, a novel water-soluble pyrazolo-[1,5-a]pyridine adenosine A1 receptor antagonist

• Published in: Bioorganic & medicinal chemistry letters Vol. 9; no. 14; pp. 1979 - 1984
• Main Authors: KURODA, S, AKAHANE, A, ITANI, H, NISHIMURA, S, DURKIN, K, KINOSHITA, T, TENDA, Y, SAKANE, K
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 19-07-1999
• Subjects: Antihypertensive Agents - chemistry; Antihypertensive Agents - pharmacology; Biological and medical sciences; Inhibitory Concentration 50; Medical sciences; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Piperidines - chemistry; Purinergic P1 Receptor Antagonists; Pyrazoles - chemistry; Pyrazoles - metabolism; Pyrazoles - pharmacology; Pyridines - chemistry; Pyridines - metabolism; Pyridines - pharmacology; Receptors, Purinergic P1 - metabolism; Solubility; Structure-Activity Relationship; Water - chemistry; Xanthines - chemistry; Xanthines - pharmacology; Rat; Angular nitrogen heterocycle; Rodentia; Central nervous system; A1 Adenosine receptor; Selectivity; In vitro; Vertebrata; Mammalia; Structure activity relation; Carboxylic acid; Animal; Bicyclic compound; Water solubility; Pyridazine derivatives; Antagonist; Chemical synthesis; Physicochemical properties; Brain (vertebrata)
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/s0960-894x(99)00304-2

Novel 3-(2-cycloalkyl and cycloalkenyl-3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazo lo [1,5-a]-pyridines were synthesized and evaluated for their adenosine A1 receptor binding activities. In this series, FR166124 (3) was found to be the most potent and selective adenosine A1 receptor antagonist, and the double bond of the cyclohexenyl acetic acid group was essential for selectivity of A1 receptor binding. Furthermore, the solubility in water of the sodium salt of FR 166124 was high.