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

Autor: Li Q; Sustainable Chemistry for Metals and Molecules (SCM-2), Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium., Claes S; 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., Verhaegen Y; Sustainable Chemistry for Metals and Molecules (SCM-2), Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium., Anthonissen S; Sustainable Chemistry for Metals and Molecules (SCM-2), Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium., Van Loy T; 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., Schols D; 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., Dehaen W; Sustainable Chemistry for Metals and Molecules (SCM-2), Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium., De Jonghe S; 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.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2023 Oct; Vol. 139, pp. 106755. Date of Electronic Publication: 2023 Jul 28.
DOI: 10.1016/j.bioorg.2023.106755
Abstrakt: 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.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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