ML221

• CAT Number: I008087
• CAS Number: 877636-42-5
• Molecular Formula: C17H11N3O6S
• Molecular Weight: 385.35
• Purity: ≥95%
• Synonyms: ML221; ML 221; ML-221.;[4-oxo-6-(pyrimidin-2-ylsulfanylmethyl)pyran-3-yl] 4-nitrobenzoate
• Target: Apelin Receptor
• Solubility: Soluble in DMSO
• Storage: Store at +4C
• IC50: 0.70 and 1.75 μM in a cAMP assay and β-arrestin assay
• IUPAC Name: [4-oxo-6-(pyrimidin-2-ylsulfanylmethyl)pyran-3-yl] 4-nitrobenzoate
• InChI: InChI=1S/C17H11N3O6S/c21-14-8-13(10-27-17-18-6-1-7-19-17)25-9-15(14)26-16(22)11-2-4-12(5-3-11)20(23)24/h1-9H,10H2
• InChIKey: UASIRTUMPRQVFY-UHFFFAOYSA-N
• SMILES: C1=CN=C(N=C1)SCC2=CC(=O)C(=CO2)OC(=O)C3=CC=C(C=C3)[N+](=O)[O-]

ML221(CAT: I008087) is an apelin receptor antagonist investigated for its potential to modulate Th1 and Th2 cell-related responses in breast cancer-bearing mice. Inhibition of apelin-related protumor activities can promote the effectiveness of cancer immunotherapy by reducing the immunosuppressive microenvironment of tumors. The combination therapy with ML221 and DC vaccination showed promising results in reducing tumor growth, preventing lung metastasis, and increasing survival rate compared to the control group. The combination treatment also increased the frequency of Th1 cells and decreased the frequency of Th2 cells in the spleen, and reduced serum levels of IL-10.

Reference

1:Bioorg Med Chem Lett. 2012 Nov 1;22(21):6656-60. doi: 10.1016/j.bmcl.2012.08.105. Epub 2012 Sep 7. 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.Maloney PR,Khan P,Hedrick M,Gosalia P,Milewski M,Li L,Roth GP,Sergienko E,Suyama E,Sugarman E,Nguyen K,Mehta A,Vasile S,Su Y,Stonich D,Nguyen H,Zeng FY,Novo AM,Vicchiarelli M,Diwan J,Chung TD,Smith LH,Pinkerton AB, PMID: 23010269 PMCID: PMC3729231 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.Copyright © 2012 Elsevier Ltd. All rights reserved.