title: Synthesis and benzodiazepine binding activity of a series of novel [1,2,4]triazolo[1,5-c]quinazolin-5(6H)-ones.
abstract: Investigation of tricyclic heterocycles related to the 2-arylpyrazolo[4,3-c]quinolin-3(5H)-ones, structures with high affinity for the benzodiazepine (BZ) receptor, led to the synthesis of 2-phenyl-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one, a compound with 4 nM binding affinity to the BZ receptor. Analogues were prepared to assess the importance of the 2-substituent and ring substitution in modifying activity. Several novel synthetic routes were designed to prepare the target compounds, including a two-step synthesis beginning with an anthranilonitrile and a hydrazide. Of the 34 compounds screened in this series, three compounds were found to be potent BZ antagonists in rat models. The leading compound, 9-chloro-2-(2-fluorophenyl) [1,2,4]triazolo[1,5- c]quinazolin-5(6H)-one (CGS 16228), showed activity comparable to that of CGS 8216 from the pyrazolo[4,3-c]quinoline series.
authors.affiliation: Research Department, CIBA-GEIGY Corporation, Summit, New Jersey 07901.
authors.forename: J E
authors.initials: JE
authors.lastname: Francis
authors.forename: W D
authors.initials: WD
authors.lastname: Cash
authors.forename: B S
authors.initials: BS
authors.lastname: Barbaz
authors.forename: P S
authors.initials: PS
authors.lastname: Bernard
authors.forename: R A
authors.initials: RA
authors.lastname: Lovell
authors.forename: G C
authors.initials: GC
authors.lastname: Mazzenga
authors.forename: R C
authors.initials: RC
authors.lastname: Friedmann
authors.forename: J L
authors.initials: JL
authors.lastname: Hyun
authors.forename: A F
authors.initials: AF
authors.lastname: Braunwalder
authors.forename: P S
authors.initials: PS
authors.lastname: Loo
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D003975:Diazepam / Q000378:metabolism; D005445:Flunitrazepam / Q000378:metabolism; D007202:Indicators and Reagents; D015394:Molecular Structure; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D007202:Indicators and Reagents; D011799:Quinazolines; D011963:Receptors, GABA-A; D014230:Triazoles; D005445:Flunitrazepam; D003975:Diazepam