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

作者：Maloney Patrick R; Khan Pasha; Hedrick Michael; Gosalia Palak; Milewski Monika; Li Linda; Roth Gregory P; Sergienko Eduard; Suyama Eigo; Sugarman Eliot; Nguyen Kevin; Mehta Alka; Vasile Stefan; Su Ying; Stonich Derek; Hung Nguyen; Zeng Fu Yue; Novo Arianna Mangravita; Vicchiarelli Michael; Diwan Jena; Chung Thomas D Y; Smith Layton H; Pinkerton Anthony B^*

来源：Bioorganic & Medicinal Chemistry Letters, 2012, 22(21): 6656-6660.

DOI：10.1016/j.bmcl.2012.08.105

• GPCRs
• HTS
• APJ
• Apelin
• Cardiovascular disease
• Antagonists
• SAR

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.

• 出版日期2012-11-1