877635-62-6Relevant articles and documents
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
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.
, p. 6656 - 6660,5 (2012/12/12)
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.
