title: Synthesis and structure--activity relationships of fused imidazopyridines: a new series of benzodiazepine receptor ligands.
abstract: 2-Arylimidazo[4,5-c]quinolines and analogous fused imidazopyridines were synthesized and evaluated as benzodiazepine receptor ligands. Affinity to the receptors was greatly affected by the bulkiness of the aryl group at the 2-position, compared to the pyrazoloquinolines such as CGS-9896. Derivatives with an isoxazole moiety at the 2-position showed high binding affinity and in vivo activity. In the imidazo[4,5-c]quinoline series, substitution at the 6-position decreased or abolished activity. Most derivatives with an unsubstituted isoxazolyl group showed antagonist or inverse agonist activity except for the 7-halo analogues, which exhibited agonist activity. On the other hand, 5-methylisoxazol-3-yl or 3-methylisoxazol-5-yl derivatives generally exhibited agonist activity. A similar substitution effect on the isoxazole moiety was observed in the imidazopyridines fused with a nonaromatic ring. From the detailed pharmacological evaluation, S-8510, 2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano++ +[4,3-b]pyridine monophosphate, possessing weak inverse agonist activity was selected as a therapeutic candidate for the treatment of some symptoms of senile dementia.
authors.affiliation: Shionogi Research Laboratories, Shionogi & Company, Ltd., Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Takada
authors.forename: T
authors.initials: T
authors.lastname: Sasatani
authors.forename: N
authors.initials: N
authors.lastname: Chomei
authors.forename: M
authors.initials: M
authors.lastname: Adachi
authors.forename: T
authors.initials: T
authors.lastname: Fujishita
authors.forename: M
authors.initials: M
authors.lastname: Eigyo
authors.forename: S
authors.initials: S
authors.lastname: Murata
authors.forename: K
authors.initials: K
authors.lastname: Kawasaki
authors.forename: A
authors.initials: A
authors.lastname: Matsushita
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D003975:Diazepam / Q000378:metabolism; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D007093:Imidazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D011725:Pyridines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D007093:Imidazoles; D008024:Ligands; D011725:Pyridines; D011804:Quinolines; D011963:Receptors, GABA-A; D003975:Diazepam