Synthesis and structure-activity relationships of 3H-quinazolin-4-ones and 3H-pyrido[2,3-d]pyrimidin-4-ones as CXCR3 receptor antagonists

CXC chemokine receptor-3 (CXCR3) is a G-protein coupled receptor (GPCR) predominantly expressed on activated T lymphocytes that promote Th1 responses. Previously, we described the 3H-quinazolin-4-one containing VUF 5834 (decanoic acid {1-[3-(4-cyano-phenyl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-ethyl}-(2-dimethylamino-ethyl)-amide) as a small-molecule CXCR3 antagonist with submicromolar affinity and as a lead structure for the development of CXCR3 antagonists. More recently, the related 3H-pyrido[2,3-d]pyrimidin-4-one compounds AMG 487 and NBI-74330 have been reported as nanomolar CXCR3 antagonists and these ligands are currently under clinical investigation. The aim of this study is to link the structure-activity relationship (SAR) of the previously published class of 3H-quinazolin-4-one containing CXCR3 ligands with these novel clinical candidates. From the modification of the lead structure VUF 5834 emerged the importance of the (4-fluoro-3-(trifluoromethyl)phenyl)acetyl and the 3-methylen-pyridine as substituents to improve the affinity at the human CXCR3 receptor, whereas other features are less important. The described molecules serve as tool to investigate the role of the CXCR3 receptor in various inflammatory conditions.