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Maloney, Patrick R.; Khan, Pasha; Hedrick, Michael; Gosalia, Palak; Milewski, Monika; Li, Linda; Roth, Gregory P.; Sergienko, Eduard; Suyama, Eigo; Sugarman, Eliot; Nguyen, Kevin; Mehta, Alka; Vasile, Stefan; Su, Ying; Stonich, Derek; Nguyen, Hung; Zeng, Fu-Yue; Novo, Arianna Mangravita; Vicchiarelli, Michael; Diwan, Jena; Chung, Thomas D.Y.; Smith, Layton H.; Pinkerton, Anthony B.
Bioorganic & medicinal chemistry letters, 11/2012, Letnik: 22, Številka: 21Journal Article
The recently discovered apelin/APJ system has emerged as a critical mediator of cardiovascular homeostasis and is associated with the pathogenesis of cardiovascular disease. A role for apelin/APJ in energy metabolism and gastrointestinal function has also recently emerged. We disclose the discovery and characterization of 4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate (ML221), a potent APJ functional antagonist in cell-based assays that is >37-fold selective over the closely related angiotensin II type 1 (AT1) receptor. The recently discovered apelin/APJ system has emerged as a critical mediator of cardiovascular homeostasis and is associated with the pathogenesis of cardiovascular disease. A role for apelin/APJ in energy metabolism and gastrointestinal function has also recently emerged. We disclose the discovery and characterization of 4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate (ML221), a potent APJ functional antagonist in cell-based assays that is >37-fold selective over the closely related angiotensin II type 1 (AT1) receptor. ML221 was derived from an HTS of the ∼330,600 compound MLSMR collection. This antagonist showed no significant binding activity against 29 other GPCRs, except to the κ-opioid and benzodiazepinone receptors (<50/<70%I at 10μM). The synthetic methodology, development of structure–activity relationship (SAR), and initial in vitro pharmacologic characterization are also presented.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Vir: Osebne bibliografije
in: SICRIS
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