title: 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.
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.
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Maloney
authors.forename: Pasha
authors.initials: P
authors.lastname: Khan
authors.forename: Michael
authors.initials: M
authors.lastname: Hedrick
authors.forename: Palak
authors.initials: P
authors.lastname: Gosalia
authors.forename: Monika
authors.initials: M
authors.lastname: Milewski
authors.forename: Linda
authors.initials: L
authors.lastname: Li
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Roth
authors.forename: Eduard
authors.initials: E
authors.lastname: Sergienko
authors.forename: Eigo
authors.initials: E
authors.lastname: Suyama
authors.forename: Eliot
authors.initials: E
authors.lastname: Sugarman
authors.forename: Kevin
authors.initials: K
authors.lastname: Nguyen
authors.forename: Alka
authors.initials: A
authors.lastname: Mehta
authors.forename: Stefan
authors.initials: S
authors.lastname: Vasile
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.forename: Derek
authors.initials: D
authors.lastname: Stonich
authors.forename: Hung
authors.initials: H
authors.lastname: Nguyen
authors.forename: Fu-Yue
authors.initials: FY
authors.lastname: Zeng
authors.forename: Arianna Mangravita
authors.initials: AM
authors.lastname: Novo
authors.forename: Michael
authors.initials: M
authors.lastname: Vicchiarelli
authors.forename: Jena
authors.initials: J
authors.lastname: Diwan
authors.forename: Thomas D Y
authors.initials: TD
authors.lastname: Chung
authors.forename: Layton H
authors.initials: LH
authors.lastname: Smith
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Pinkerton
mesh_terms: D000818:Animals; D000075244:Apelin Receptors; D002317:Cardiovascular Agents / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D022781:Hepatocytes / Q000187:drug effects; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D009579:Nitrobenzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C578927:4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate; C104575:APLNR protein, human; D000075244:Apelin Receptors; D002317:Cardiovascular Agents; D009579:Nitrobenzoates; D011714:Pyrans; D043562:Receptors, G-Protein-Coupled