title: Design, synthesis, and structure-activity relationships of potent GPIIb/IIIa antagonists: discovery of FK419.
abstract: The discovery of the non-peptide antiplatelet injectable agent FK419 is reported. Based on the beta-turn structure of RGD peptide sequences in the alpha chain of fibrinogen, which binds the glycoprotein IIb/IIIa (GPIIb/IIIa) on the surface of platelets to induce platelet aggregation, the prototype 2 was designed. After further substituent effects were investigated at the alpha-position of the carboxylic acid in 2, we enhanced platelet aggregation inhibition, and discovered the useful feature of reduced prolongation of bleeding time. Finally, the potent platelet aggregation inhibitor FK419 (3) could be discovered. FK419 shows a safe feature of reduced prolongation of bleeding time, as well as potent inhibition of platelet aggregation.
authors.affiliation: Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd, 2-1-6 Kashima, Yodogawa-Ku, Osaka 532-8514, Japan. toshio.yamanaka@jp.astellas.com
authors.forename: Toshio
authors.initials: T
authors.lastname: Yamanaka
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ohkubo
authors.forename: Satoru
authors.initials: S
authors.lastname: Kuroda
authors.forename: Hideko
authors.initials: H
authors.lastname: Nakamura
authors.forename: Fumie
authors.initials: F
authors.lastname: Takahashi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Aoki
authors.forename: Kayoko
authors.initials: K
authors.lastname: Mihara
authors.forename: Jiro
authors.initials: J
authors.lastname: Seki
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kato
mesh_terms: D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008297:Male; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: C496616:((S)-2-acetylamino-3-((R)-(1-(3-(piperidin-4-yl)propionyl)piperidin-3-ylcarbonyl))amino) propionic acid trihydrate; D009842:Oligopeptides; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011422:Propionates; D014841:von Willebrand Factor; C047981:arginyl-glycyl-aspartic acid