Synthesis and structure-activity relationship study of phenoxybenzylpiperazine analogues as CCR8 agonists

Qifei Li; Sandra Claes; Yenthel Verhaegen; Stijn Anthonissen; Tom Van Loy; Dominique Schols; Wim Dehaen; Steven De Jonghe

doi:10.1016/j.bioorg.2023.106755

Synthesis and structure-activity relationship study of phenoxybenzylpiperazine analogues as CCR8 agonists

Bioorg Chem. 2023 Oct:139:106755. doi: 10.1016/j.bioorg.2023.106755. Epub 2023 Jul 28.

Authors

Qifei Li¹, Sandra Claes², Yenthel Verhaegen¹, Stijn Anthonissen¹, Tom Van Loy², Dominique Schols², Wim Dehaen¹, Steven De Jonghe³

Affiliations

¹ Sustainable Chemistry for Metals and Molecules (SCM-2), Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium.
² KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, box 1043, B-3000 Leuven, Belgium.
³ KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, box 1043, B-3000 Leuven, Belgium. Electronic address: steven.dejonghe@kuleuven.be.

PMID: 37544272
DOI: 10.1016/j.bioorg.2023.106755

Abstract

CCR8 agonists hold promise for the treatment of various auto-immune diseases. Despite the fact that phenoxybenzylpiperazine derivatives are known to be endowed with CCR8 agonistic activity, systematic structure-activity relationship studies have not been reported. In this study, ZK756326, a previously disclosed CCR8 agonist, was divided in various fragments and each subunit was subjected to structural modifications. All newly synthesized analogues were evaluated in a CCR8 calcium mobilization assay, revealing that only limited structural variation was tolerated in both phenyl rings and at the benzylic position. In contrast, various linkers gave analogues with good CCR8 agonistic potency. In addition, the presence of small substituents on the piperazinyl moiety or the exchange of the piperazinyl for a piperidinyl group afforded compounds with promising CCR8 agonism, with the most potent congener being 10-fold more potent than ZK756326.

Keywords: Agonist; CCR8; Phenoxybenzylpiperazine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Receptors, CCR8* / antagonists & inhibitors
Signal Transduction*
Structure-Activity Relationship

Substances

Receptors, CCR8
2-(2-(4-(3-phenoxybenzyl)piperazin-1-yl)ethoxy)ethanol