title: Novel adenosine A1 receptor antagonists. Synthesis and structure-activity relationships of a novel series of 3-(2-cyclohexenyl-3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5 -a]pyridines.
abstract: A novel series of 3-(2-cyclohexenyl-3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazol o[1,5-a]pyridines was synthesized and evaluated for in vitro adenosine A1 and A2A receptor binding activities. Most of the cyclohexenyl derivatives (7a-e, 8a-s) were found to be potent adenosine A1 receptor antagonists. In a series of analogues of FR166124 (3a), alcohol 7c, nitrile 7e and amide derivatives (7d, 8c, 8r) were found to be more potent A1 antagonists with higher A2A/A1 selectivity than FR166124. Amongst them, 8r showed considerable water solubility (33.3 mg/mL), but lower than that of the sodium salt of FR166124 (> 200 mg/mL). Additionally, FR166124 had strong diuretic activity by both p.o. and iv administration in rats (minimum effective dose=0.1 and 0.032 mg/kg, respectively).
authors.affiliation: Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan. satoru_kuroda@po.fujisawa.co.jp
authors.forename: S
authors.initials: S
authors.lastname: Kuroda
authors.forename: A
authors.initials: A
authors.lastname: Akahane
authors.forename: H
authors.initials: H
authors.lastname: Itani
authors.forename: S
authors.initials: S
authors.lastname: Nishimura
authors.forename: K
authors.initials: K
authors.lastname: Durkin
authors.forename: Y
authors.initials: Y
authors.lastname: Tenda
authors.forename: K
authors.initials: K
authors.lastname: Sakane
mesh_terms: D000818:Animals; D004232:Diuretics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship
chemical_list: D004232:Diuretics; C121286:FR 166124; D058915:Purinergic P1 Receptor Antagonists; D011720:Pyrazoles; D011725:Pyridines