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
  • 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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