title: Identification of high-affinity P2Y₁₂ antagonists based on a phenylpyrazole glutamic acid piperazine backbone.
abstract: A series of novel, highly potent P2Y₁₂ antagonists as inhibitors of platelet aggregation based on a phenylpyrazole glutamic acid piperazine backbone is described. Exploration of the structural requirements of the substituents by probing the structure-activity relationship along this backbone led to the discovery of the N-acetyl-(S)-proline cyclobutyl amide moiety as a highly privileged motif. Combining the most favorable substituents led to remarkably potent P2Y₁₂ antagonists displaying not only low nanomolar binding affinity to the P2Y₁₂ receptor but also a low nanomolar inhibition of platelet aggregation in the human platelet rich plasma assay with IC₅₀ values below 50 nM. Using a homology and a three-dimensional quantitative structure-activity relationship model, a binding hypothesis elucidating the impact of several structural features was developed.
authors.affiliation: Sanofi-Aventis Deutschland GmbH , Industriepark Höchst, Building G878, D-65926 Frankfurt am Main, Germany.
authors.forename: Gernot
authors.initials: G
authors.lastname: Zech
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hessler
authors.forename: Andreas
authors.initials: A
authors.lastname: Evers
authors.forename: Tilo
authors.initials: T
authors.lastname: Weiss
authors.forename: Peter
authors.initials: P
authors.lastname: Florian
authors.forename: Melitta
authors.initials: M
authors.lastname: Just
authors.forename: Jörg
authors.initials: J
authors.lastname: Czech
authors.forename: Werngard
authors.initials: W
authors.lastname: Czechtizky
authors.forename: Jochen
authors.initials: J
authors.lastname: Görlitzer
authors.forename: Sven
authors.initials: S
authors.lastname: Ruf
authors.forename: Markus
authors.initials: M
authors.lastname: Kohlmann
authors.forename: Marc
authors.initials: M
authors.lastname: Nazaré
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D058921:Purinergic P2Y Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: C548576:P2RY12 protein, human; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D011720:Pyrazoles; D058925:Receptors, Purinergic P2Y12; D018698:Glutamic Acid