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Issue 1, 2010
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Histamine H3receptor ligands with a 3-cyclobutoxy motif: a novel and versatile constraint of the classical 3-propoxy linker

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Abstract

Antagonists/inverse agonists for the histamine H3 receptor (H3R) are subject to intensive research. Many chemical classes contain a 3-propoxy linker to connect an aromatic moiety and a basic amine. Rigidifying this linker by several moieties has proven successful. However, so far, a 3-cyclobutoxy constraint has not been disclosed in H3R research. Here, we present novel synthetic methodology toward compounds with this functionality. A condensation between piperidine and 1,3-cyclobutanedione followed by a reduction furnishes a versatile cis-3-piperidino-cyclobutanol building block which allows ready access to constrained compounds having a 3-piperidino-cyclobutoxy moiety. Pharmacological studies reveal that this particular rigidification leads to a significant increase in H3R affinity compared to the non-constrained counterpart. In all, the constrained 3-cyclobutoxy linker emerges as a novel, versatile and attractive motif for H3R ligands.

Graphical abstract: Histamine H3 receptor ligands with a 3-cyclobutoxy motif: a novel and versatile constraint of the classical 3-propoxy linker

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Publication details

The article was received on 24 Apr 2010, accepted on 09 Jun 2010 and first published on 18 Jun 2010


Article type: Concise Article
DOI: 10.1039/C0MD00056F
Med. Chem. Commun., 2010,1, 39-44

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    Histamine H3 receptor ligands with a 3-cyclobutoxy motif: a novel and versatile constraint of the classical 3-propoxy linker

    M. Wijtmans, F. Denonne, S. Célanire, M. Gillard, S. Hulscher, C. Delaunoy, N. Van houtvin, R. A. Bakker, S. Defays, J. Gérard, L. Grooters, D. Hubert, H. Timmerman, R. Leurs, P. Talaga, I. J. P. de Esch and L. Provins, Med. Chem. Commun., 2010, 1, 39
    DOI: 10.1039/C0MD00056F

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