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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:22

Article

Maloney, Patrick R.²  Khan, Pasha²  Hedrick, Michael¹  Gosalia, Palak¹  Milewski, Monika¹  Li, Linda¹  Roth, Gregory P.²  Sergienko, Eduard¹  Suyama, Eigo²  Sugarman, Eliot²  Nguyen, Kevin²  Mehta, Alka²  Vasile, Stefan²  Su, Ying¹  Stonich, Derek¹  Hung Nguyen¹  Zeng, Fu-Yue¹  Novo, Arianna Mangravita²  Vicchiarelli, Michael²  Diwan, Jena¹  Chung, Thomas D. Y.¹  Smith, Layton H.^2,3  Pinkerton, Anthony B.¹ 

[1] Sanford Burnham Med Res Inst, Conrad Prebys Ctr Chem Genom, La Jolla, CA 92037 USA

[2] Sanford Burnham Med Res Inst, Conrad Prebys Ctr Chem Genom, Orlando, FL 32827 USA

[3] Sanford Burnham Med Res Inst Lake Nona, Diabet & Obes Res Ctr, Cardiopathobiol Program, Orlando, FL 32827 USA

关键词: GPCRs;    HTS;    APJ;    Apelin;    Cardiovascular disease;    Antagonists;    SAR;   

DOI  :  10.1016/j.bmcl.2012.08.105

来源: Elsevier

【 摘 要 】

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 similar to 330,600 compound MLSMR collection. This antagonist showed no significant binding activity against 29 other GPCRs, except to the kappa-opioid and benzodiazepinone receptors (<50/<70%I at 10 mu M). The synthetic methodology, development of structure-activity relationship (SAR), and initial in vitro pharmacologic characterization are also presented. (C) 2012 Elsevier Ltd. All rights reserved.

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