The P2Y2 receptor (P2Y2R) has been implicated in a range of clinical conditions, including but not limited to: cystic fibrosis, dry eye syndrome and cancer. However, a lack of high quality, drug-like modulators and tool-like compounds means there is scope to develop ligands that can further probe P2Y2R function in vitro and in vivo. Assessment of the reported P2Y2R antagonists led to the conclusion that 5-((5-(2,8-dimethyl-5H-dibenzo[a,d][7]annulen-5-yl)-2-oxo-4-thioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-(1H-tetrazol-5-yl)furan-2-carboxamide (AR-C118925, 38) was the most drug-like P2Y2R antagonist and was chosen as a chemical starting point. Elaboration of the 2,8-dimethyl-5H-dibenzo[a,d]cyclohepten-5-yl moeity to a 7-chloro-2-methyl-4H-benzo[5,6]cyclohepta[1,2-d]thiazol-4-yl), led to the development of two potent, novel P2Y2R antagonists: MSG204 105 (pKB = 6.73 0.25, n = 3) and MSG249 119 (pKB = 7.06 0.02, n = 3), both of which exhibit improved physicochemical properties to AR-C118925 38 and provide more drug-like alternatives for future in vivo work. Structure activity relationships derived in developing these novel P2Y2R antagonists, has ultimately led to the development of multiple fluorescently-labelled P2Y2R ligands. Most notably, BODIPY 630/650 conjugate MSG260 193 (pKd = 6.99 0.04, n = 3) and BODIPY FL conjugate MSG262 195 (pKd = 6.88 0.01, n = 3), which have enabled the use of a novel P2Y2R BRET ligand-binding assay and provide a robust platform for future drug discovery programs.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:757410 |
| Date | January 2018 |
| Creators | Conroy, S. |
| Publisher | University of Nottingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://eprints.nottingham.ac.uk/51072/ |
Page generated in 0.0101 seconds