Histamine H3 receptor ligands with a 3-cyclobutoxy motif: a novel and versatile constraint of the classical 3-propoxy linker
| Autor: | Laurent Provins, Luc Grooters, Henk Timmerman, Iwan J. P. de Esch, Maikel Wijtmans, Sylvain Celanire, Julien Gérard, Patrice Talaga, Michel Gillard, Frédéric Denonne, Delphine Hubert, Remko A. Bakker, Saskia Hulscher, Sabine Defays, Christel Delaunoy, Rob Leurs, Nathalie Van houtvin |
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| Přispěvatelé: | Medicinal chemistry, AIMMS |
| Rok vydání: | 2010 |
| Předmět: |
Pharmacology
Stereochemistry Organic Chemistry Pharmaceutical Science Biochemistry Combinatorial chemistry chemistry.chemical_compound SDG 3 - Good Health and Well-being chemistry Drug Discovery Molecular Medicine Inverse agonist Moiety Amine gas treating Aromatic moiety Piperidine Histamine H3 receptor Linker |
| Zdroj: | MedChemComm, 1, 39-44. Royal Society of Chemistry Wijtmans, M, Denonne, F, Célanire, S, Gillard, M, Hulscher, T M, Delaunoy, C, Van Houtvin, N, Bakker, R A, Defays, S, Gérard, J, Grooters, L, Hubert, D, Timmerman, H, Leurs, R, Talaga, P, De Esch, I J & Provins, L 2010, ' Histamine H3 receptor ligands with a 3-cyclobutoxy motif: a novel and versatile constraint of the classical 3-propoxy linker ', MedChemComm, vol. 1, pp. 39-44 . https://doi.org/10.1039/c0md00056f |
| ISSN: | 2040-2511 2040-2503 |
| DOI: | 10.1039/c0md00056f |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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