title: Triazolobenzo- and triazolothienodiazepines as potent antagonists of platelet activating factor.
abstract: A series of [1,2,4]triazolo[4,3-alpha][1,4]benzodiazepines bearing an ethynyl functionality at the 8-position and the isosteric thieno[3,2-f][1,2,4]triazolo[4,3-alpha][1,4]diazepines were prepared and evaluated as antagonists of platelet activating factor. The effects of substitution were explored in in vitro and in vivo test systems designed to measured PAF-antagonistic activity. Results are discussed and compared with previously published data. Many of the compounds had activity superior to WEB 2086, compound 1. In general, the thieno analogues exhibited better oral activity than the corresponding benzodiazepines. The duration of activity upon oral administration was modulated by the substitution on the acetylenic side chain. Compounds 71 and 81 were selected for further pharmacological evaluation as a result of their good oral potency and exceptionally long duration of action.
authors.affiliation: Chemistry Research Department, Roche Research Center, Hoffmann-La Roche, Incorporated, Nutley, New Jersey 07110.
authors.forename: A
authors.initials: A
authors.lastname: Walser
authors.forename: T
authors.initials: T
authors.lastname: Flynn
authors.forename: C
authors.initials: C
authors.lastname: Mason
authors.forename: H
authors.initials: H
authors.lastname: Crowley
authors.forename: C
authors.initials: C
authors.lastname: Maresca
authors.forename: B
authors.initials: B
authors.lastname: Yaremko
authors.forename: M
authors.initials: M
authors.lastname: O'Donnell
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis / Q000494:pharmacology*; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000494:pharmacology*; D001792:Blood Platelets / Q000378:metabolism; D016084:Bronchoconstriction / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D006168:Guinea Pigs; D008297:Male; D008968:Molecular Conformation; D015394:Molecular Structure; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology*; D014230:Triazoles / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D001381:Azepines; D010972:Platelet Activating Factor; D013876:Thiophenes; D014230:Triazoles; C052518:WEB 2086; D001569:Benzodiazepines