ArticleBioorganic & medicinal chemistry letters2012
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.
Article in Bioorganic & medicinal chemistry letters, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 62 citations in OpenAlex.
- International Union of Basic and Clinical Pharmacology. CXXI. Apelin receptor pharmacology in the human cardiovascular system and emerging clinical applications.Pharmacological reviews · 2026Review
- The Apelinergic System in Kidney Disease: Novel Perspectives.International journal of molecular sciences · 2025Review
- Novel small molecule analogs for advancing apelin receptor antagonism with enhanced plasma and microsomal stability.Bioorganic & medicinal chemistry letters · 2025Article
- Apelin/APJ: Another Player in the Cancer Biology Network.International journal of molecular sciences · 2025Review
- Article
- Targeting APLN/APJ restores blood-testis barrier and improves spermatogenesis in murine and human diabetic models.Nature communications · 2022Article
- (-)-Epicatechin Is a Biased Ligand of Apelin Receptor.International journal of molecular sciences · 2022Article
- The Role of Apelin-APJ System in Diabetes and Obesity.Frontiers in endocrinology · 2022Review
- The Apelin-Apelin Receptor Axis Triggers Cholangiocyte Proliferation and Liver Fibrosis During Mouse Models of Cholestasis.Hepatology (Baltimore, Md.) · 2021Article
- The apelinergic system: a perspective on challenges and opportunities in cardiovascular and metabolic disorders.Annals of the New York Academy of Sciences · 2019Review
- International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand.Pharmacological reviews · 2019Review
- Apelin/APJ system: A potential therapeutic target for endothelial dysfunction-related diseases.Journal of cellular physiology · 2019Review
- Multifunctional APJ Pathway Promotes Ovarian Cancer Progression and Metastasis.Molecular cancer research : MCR · 2019Article
- APLN promotes hepatocellular carcinoma through activating PI3K/Akt pathway and is a druggable target.Theranostics · 2019Article
- Vascular effects of apelin: Mechanisms and therapeutic potential.Pharmacology & therapeutics · 2018Review
- Article
- The Role of Apelin in Cardiovascular Diseases, Obesity and Cancer.Frontiers in physiology · 2018Review
- Repurposing antimalarial aminoquinolines and related compounds for treatment of retinal neovascularization.PloS one · 2018Article
- An apelin receptor antagonist prevents pathological retinal angiogenesis with ischemic retinopathy in mice.Scientific reports · 2017Article
- Effect of the spinal apelin‑APJ system on the pathogenesis of chronic constriction injury‑induced neuropathic pain in rats.Molecular medicine reports · 2017Article
Corrections and comments
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Authors and funding
23 authors at 1 institution in 1 country.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.