- Discovery of 4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate (ML221) as a functional antagonist of the apelin (APJ) receptor
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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 10 μM). The synthetic methodology, development of structure-activity relationship (SAR), and initial in vitro pharmacologic characterization are also presented.
- Maloney, Patrick R.,Khan, Pasha,Roth, Gregory P.,Suyama, Eigo,Sugarman, Eliot,Nguyen, Kevin,Mehta, Alka,Vasile, Stefan,Novo, Arianna Mangravita,Vicchiarelli, Michael,Smith, Layton H.,Hedrick, Michael,Gosalia, Palak,Milewski, Monika,Li, Linda,Sergienko, Eduard,Su, Ying,Stonich, Derek,Nguyen, Hung,Zeng, Fu-Yue,Diwan, Jena,Chung, Thomas D. Y.,Pinkerton, Anthony B.
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p. 6656 - 6660,5
(2012/12/12)
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