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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| Affiliation: | 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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