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Synthesis and Structure‐Activity Relationships of 3 H ‐Quinazolin‐4‐ones and 3 H ‐Pyrido[2,3‐ d ]pyrimidin‐4‐ones as CXCR3 receptor antagonists
Author(s) -
Storelli Stefania,
Verzijl Dennis,
AlBadie Jawad,
Elders Niels,
Bosch Leontien,
Timmerman Henk,
Smit Martine J.,
De Esch Iwan J. P.,
Leurs Rob
Publication year - 2007
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.200700037
Subject(s) - chemistry , cxcr3 , stereochemistry , receptor , antagonist , trifluoromethyl , pyridine , structure–activity relationship , pharmacology , chemokine receptor , biochemistry , chemokine , medicinal chemistry , in vitro , biology , organic chemistry , alkyl
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 3 H ‐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 3 H ‐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 3 H ‐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.