title: New platelet aggregation inhibitors based on pyridazinone moiety.
abstract: New series of pyridazinone derivatives (4, 5 and 6) were synthesized in good yields following a synthetic strategy based on singlet oxygen oxidation of alkyl furans, in which a suitable β(α)-substituted γ-hydroxybutenolide (10 or 11) or a bicyclic lactone (12 or 13) was the key intermediate. The synthesized compounds were tested in vitro as antiplatelet agents and some of them (compounds 4b, 4d and 5b) exhibited potent inhibitory effects on collagen-induced platelet aggregation with IC50 values in the low μM range. Studies performed with the most active compound of these series (4b) demonstrated its lack of activity as inhibitor of platelet aggregation induced by other agonists as thrombin, ionomycin or U-46619 suggesting a selective action on the biochemical mechanisms triggered by collagen in the platelets.
authors.affiliation: Departamento de Química Orgánica, Universidade de Vigo, 36310 Vigo, Spain; Instituto de Investigación Biomédica (IBI), Universidade de Vigo, 36310 Vigo, Spain.
authors.forename: Tamara
authors.initials: T
authors.lastname: Costas
authors.affiliation: Departamento de Química Orgánica, Universidade de Vigo, 36310 Vigo, Spain; Instituto de Investigación Biomédica (IBI), Universidade de Vigo, 36310 Vigo, Spain.
authors.forename: María Carmen
authors.initials: MC
authors.lastname: Costas-Lago
authors.affiliation: Departamento de Química Orgánica, Universidade de Vigo, 36310 Vigo, Spain; Instituto de Investigación Biomédica (IBI), Universidade de Vigo, 36310 Vigo, Spain.
authors.forename: Noemí
authors.initials: N
authors.lastname: Vila
authors.affiliation: Departamento de Química Orgánica, Universidade de Vigo, 36310 Vigo, Spain; Instituto de Investigación Biomédica (IBI), Universidade de Vigo, 36310 Vigo, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Besada
authors.affiliation: Departamento de Farmacoloxía, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Cano
authors.affiliation: Departamento de Química Orgánica, Universidade de Vigo, 36310 Vigo, Spain; Instituto de Investigación Biomédica (IBI), Universidade de Vigo, 36310 Vigo, Spain. Electronic address: mcteran@uvigo.es.
authors.forename: Carmen
authors.initials: C
authors.lastname: Terán
mesh_terms: D001792:Blood Platelets / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D003094:Collagen / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D010766:Phosphorylation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011724:Pyridazines / Q000737:chemistry; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism
chemical_list: D010975:Platelet Aggregation Inhibitors; D011724:Pyridazines; D014443:Tyrosine; C062482:pyridazine; D003094:Collagen; D013917:Thrombin
keywords: 3-Alkylfuran; Bicyclic lactone; Butenolide; Platelet aggregation inhibitors; Pyridazinone; Singlet oxygen