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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| Authors: | Patrick R Maloney Pasha Khan Michael Hedrick Palak Gosalia Monika Milewski Linda Li Gregory P Roth Eduard Sergienko Eigo Suyama Eliot Sugarman Kevin Nguyen Alka Mehta Stefan Vasile Ying Su Derek Stonich Hung Nguyen Fu-Yue Zeng Arianna Mangravita Novo Michael Vicchiarelli Jena Diwan Anthony B Pinkerton |
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| Institution: | 1. Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, USA;2. Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA;3. Cardiopathobiology Program, Diabetes and Obesity Research Center, Sanford Burnham Medical Research Institute at Lake Nona, 6400 Sanger Road, Orlando, FL 32827, USA |
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| Abstract: | 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. |
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| Keywords: | GPCRs HTS APJ Apelin Cardiovascular disease Antagonists SAR |
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