2. Academic Validation
  3. 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

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

  • Bioorg Med Chem Lett. 2012 Nov 1;22(21):6656-60. doi: 10.1016/j.bmcl.2012.08.105.
Patrick R Maloney 1,  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,  Thomas D Y Chung,  Layton H Smith,  Anthony B Pinkerton
Affiliations

Affiliation

  • 1 Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, USA.
PMID: 23010269 DOI: 10.1016/j.bmcl.2012.08.105
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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