title: Potent, long-acting cyclopentane-1,3-Dione thromboxane (A2)-receptor antagonists.
abstract: A series of derivatives of the known thromboxane A2 prostanoid (TP) receptor antagonists, 3-(6-((4-chlorophenyl)sulfonamido)-5,6,7,8-tetrahydronaphthalen-1-yl)propanoic acid and 3-(3-(2-((4-chlorophenyl)sulfonamido)ethyl)phenyl) propanoic acid, were synthesized in which the carboxylic acid functional group was replaced with substituted cyclopentane-1,3-dione (CPD) bioisosteres. Characterization of these molecules led to the discovery of remarkably potent new analogues, some of which were considerably more active than the corresponding parent carboxylic acid compounds. Depending on the choice of the C2 substituent of the CPD unit, these new derivatives can produce either a reversible or an apparent irreversible inhibition of the human TP receptor. Given the potency and the long-lasting inhibition of TP receptor signaling, these novel antagonists may comprise promising leads for the development of antithromboxane therapies.
authors.affiliation: Department of Chemistry, School of Arts and Sciences, and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Xiaozhao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Chemistry, School of Arts and Sciences, and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Chemistry, School of Arts and Sciences, and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Longchuan
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Chemistry, School of Arts and Sciences, and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Katie
authors.initials: K
authors.lastname: Herbst-Robinson
authors.affiliation: Department of Chemistry, School of Arts and Sciences, and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Cornec
authors.affiliation: Department of Chemistry, School of Arts and Sciences, and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: James
authors.affiliation: Department of Chemistry, School of Arts and Sciences, and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Shimpei
authors.initials: S
authors.lastname: Sugiyama
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University , King Edward VII Avenue, Cardiff CF10 3NB, United Kingdom.
authors.forename: Marcella
authors.initials: M
authors.lastname: Bassetto
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University , King Edward VII Avenue, Cardiff CF10 3NB, United Kingdom.
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.affiliation: Department of Chemistry, School of Arts and Sciences, and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Department of Chemistry, School of Arts and Sciences, and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.affiliation: Department of Chemistry, School of Arts and Sciences, and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.affiliation: Department of Chemistry, School of Arts and Sciences, and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Brunden
authors.affiliation: Department of Chemistry, School of Arts and Sciences, and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States ; Department of Chemistry, School of Arts and Sciences, and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Carlo
authors.initials: C
authors.lastname: Ballatore
keywords: Cyclopentane-1,3-dione; carboxylic acid bioisostere; thromboxane A2; thromboxane receptor antagonists