Multistep Continuous-Flow Synthesis in Medicinal Chemistry: Discovery and Preliminary Structure–Activity Relationships of CCR8 Ligands

Authors

  • Dr. Trine P. Petersen,

    1. Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense M (Denmark)
    2. Discovery Chemistry & DMPK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby (Denmark)
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  • Sahar Mirsharghi,

    1. Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense M (Denmark)
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  • Dr. Pia C. Rummel,

    1. Laboratory for Molecular Pharmacology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N (Denmark)
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  • Dr. Stefanie Thiele,

    1. Laboratory for Molecular Pharmacology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N (Denmark)
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  • Prof. Dr. Mette M. Rosenkilde,

    1. Laboratory for Molecular Pharmacology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N (Denmark)
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  • Dr. Andreas Ritzén,

    Corresponding author
    1. Discovery Chemistry & DMPK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby (Denmark)
    2. Present address: Medicinal Chemistry II, LEO Pharma A/S, Industriparken 55, 2750 Ballerup (Denmark)
    • Discovery Chemistry & DMPK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby (Denmark)
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  • Prof. Dr. Trond Ulven

    Corresponding author
    1. Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense M (Denmark)
    • Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense M (Denmark)
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Abstract

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.

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