Master of Science, University of Bristol (2012)
Doctor of Philosophy, Imperial College of Science, Technology & Medicine (2017)
View details for Web of Science ID 000468965200248
View details for Web of Science ID 000468965200450
With the goal of discovering more selective anti-inflammatory drugs, than COX inhibitors, to attenuate prostaglandin signaling, a fragment-based screen of hematopoietic prostaglandin D synthase was performed. The 76 crystallographic hits were sorted into similar groups, with the 3-cyano-quinoline 1a (FP IC50?=?220,000?nM, LE?=?0.43) being a potent member of the 6,6-fused heterocyclic cluster. Employing SAR insights gained from structural comparisons of other H-PGDS fragment binding mode clusters, the initial hit 1a was converted into the 70-fold more potent quinoline 1d (IC50?=?3,100?nM, LE?=?0.49). A systematic substitution of the amine moiety of 1d, utilizing structural information and array chemistry, with modifications to improve inhibitor stability, resulted in the identification of the 300-fold more active H-PGDS inhibitor tool compound 1bv (IC50?=?9.9?nM, LE?=?0.42). This selective inhibitor exhibited good murine pharmacokinetics, dose-dependently attenuated PGD2 production in a mast cell degranulation assay and should be suitable to further explore H-PGDS biology.
View details for DOI 10.1016/j.bmc.2019.02.017
View details for PubMedID 30858025
The development of a novel electrochemical methodology to generate carbon-11 carbon monoxide ([(11)C]CO) from cyclotron-produced carbon-11 carbon dioxide ([(11)C]CO2) using Ni(cyclam) and Zn(cyclen) complexes is described. This methodology allows up to 10% yields of [(11)C]CO from [(11)C]CO2. Produced [(11)C]CO was subsequently converted to [(11)C]N-benzylbenzamide under mild conditions with a radiochemical purity (RCP) of >98%.
View details for DOI 10.1039/c7cc00319f
View details for PubMedID 28234400