title: Structure-activity studies on diphenylpyrazine derivatives: a novel class of prostacyclin receptor agonists.
abstract: To develop nonprostanoid prostacyclin receptor agonists with a high degree of metabolic resistance and an extended duration of action, a novel series of diphenylpyrazine derivatives was synthesized and evaluated for their inhibition of ADP-induced human platelet aggregation. Structure-activity relationship studies on the side chain containing the carboxylic acid moiety of the lead compound 5c showed that the length of the linker and the presence of the concatenating nitrogen atom adjacent to the pyrazine ring are critical for the antiaggregatory activity. This study led to the discovery of 2-amino-5,6-diphenylpyrazine derivatives 8c, 15a, and 15b, which showed potent inhibition of platelet aggregation with IC(50) values of 0.2 microM. Among these compounds, 15b is an orally available and long-lasting prostacyclin receptor agonist which is promising for the treatment of various vascular diseases.
authors.affiliation: Discovery Research Laboratories, Nippon Shinyaku Co Ltd, Kisshoin, Kyoto, Japan. t.asaki@po.nippon-shinyaku.co.jp
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Asaki
authors.forename: Taisuke
authors.initials: T
authors.lastname: Hamamoto
authors.forename: Yukiteru
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kuwano
authors.forename: Kenji
authors.initials: K
authors.lastname: Kuwabara
mesh_terms: D006801:Humans; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D044006:Receptors, Epoprostenol / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D011719:Pyrazines; D044006:Receptors, Epoprostenol