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Multistep Continuous‐Flow Synthesis in Medicinal Chemistry: Discovery and Preliminary Structure–Activity Relationships of CCR8 Ligands
Author(s) -
Petersen Trine P.,
Mirsharghi Sahar,
Rummel Pia C.,
Thiele Stefanie,
Rosenkilde Mette M.,
Ritzén Andreas,
Ulven Trond
Publication year - 2013
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201204350
Subject(s) - agonist , modular design , continuous flow , chemistry , combinatorial chemistry , computational biology , ligand (biochemistry) , scope (computer science) , sequence (biology) , structure–activity relationship , stereochemistry , in vitro , computer science , receptor , biochemistry , biology , biochemical engineering , engineering , programming language
A three‐step continuous‐flow synthesis system and its application to the assembly of a new series of chemokine receptor ligands directly from commercial building blocks is reported. No scavenger columns or solvent switches are necessary to recover the desired test compounds, which were obtained in overall yields of 49–94 %. The system is modular and flexible, and the individual steps of the sequence can be interchanged with similar outcome, extending the scope of the chemistry. Biological evaluation confirmed activity on the chemokine CCR8 receptor and provided initial structure–activity‐relationship (SAR) information for this new ligand series, with the most potent member displaying full agonist activity with single‐digit nanomolar potency. To the best of our knowledge, this represents the first published example of efficient use of multistep flow synthesis combined with biological testing and SAR studies in medicinal chemistry.