4-benzyl-1H-imidazoles with oxazoline termini as histamine H3 receptor agonists
| Autor: | Bernard Christophe, Philippe P. Collart, Bastiaan J. Venhuis, Maikel Wijtmans, Saskia Hulscher, Benedicte Lallemand, Edith Gelens, Patrice Talaga, Iwan J. P. de Esch, Michel Gillard, Erwin Snip, Sylvain Celanire, Henk Timmerman, Rob Leurs, Henk van der Goot, Florence Lebon, Remko A. Bakker |
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| Přispěvatelé: | Medicinal chemistry, Organic Chemistry, Chemistry and Pharmaceutical Sciences |
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Agonist
Models Molecular medicine.drug_class Stereochemistry Guinea Pigs Alkyne Oxazoline CHO Cells In Vitro Techniques Chemical synthesis Histamine Agonists chemistry.chemical_compound Radioligand Assay Structure-Activity Relationship Cricetulus Cytochrome P-450 Enzyme System SDG 3 - Good Health and Well-being Cricetinae Drug Discovery medicine Inverse agonist Animals Combinatorial Chemistry Techniques Humans Receptors Histamine H3 Oxazoles chemistry.chemical_classification Imidazoles Muscle Smooth Ligand (biochemistry) Affinities Intestines chemistry Drug Design Molecular Medicine Histamine H3 receptor Muscle Contraction Protein Binding |
| Zdroj: | Wijtmans, M, Celanire, S, Snip, E, Gillard, M R, Gelens, E, Collart, P P, Venhuis, B J, Christophe, B, Hulscher, ST, van der Goot, H, Lebon, F, Timmerman, H, Bakker, R A, Leurs, R, Lallemand, B I, Talaga, P & de Esch, I J P 2008, ' 4-benzyl-1H-imidazoles with oxazoline termini as histamine H3 receptor agonists ', Journal of Medicinal Chemistry, vol. 51, no. 10, pp. 2944-53 . https://doi.org/10.1021/jm7014149 Journal of Medicinal Chemistry, 51(10), 2944-53. American Chemical Society |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm7014149 |
| Popis: | Research on the therapeutic applications of the histamine H3 receptor (H3R) has traditionally focused on antagonists/inverse agonists. In contrast, H3R agonists have received less attention despite their potential use in several disease areas. The lower availability of H3R agonists not only hampers their full therapeutic exploration, it also prevents an unequivocal understanding of the structural requirements for H3R activation. In the light of these important issues, we present our findings on 4-benzyl-1H-imidazole-based H3R agonists. Starting from two high throughput screen hits (10 and 11), the benzyl side chain was altered with lipophilic groups using combinatorial and classical chemical approaches (compounds 12-31). Alkyne- or oxazolino-substituents gave excellent affinities and agonist activities up to the single digit nM range. Our findings further substantiate the growing notion that basic ligand sidechains are not necessary for H 3R activation and reveal the oxazolino group as a hitherto unexplored functional group in H3R research. |
| Databáze: | OpenAIRE |
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