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Laurent Provins,
Frédéric Denonne,
Sylvain Célanire, Bernard Christophe,
Sabine Defays,
Christel Delaunoy,
Marie-Laure Delporte,
Thierry Demaude,
Véronique Durieu,
Michel Gillard,
Delphine Hubert,
Yves Lamberty,
Geneviève Lorent,
Anne Valade,
Alain Vanbellinghen,
Nathalie Van Houtvin
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ABSTRACT: The simpler, the better: H(3) histamine receptor (H(3) R) are of interest as therapeutic targets in cognitive and somnolence disorders. Here, lead optimization of H(3) R inverse agonists bearing a thiazolo[5,4-c]piperidine group gave rise to a clinical candidate with a much simpler unprecedented benzamide scaffold, displaying decreased hERG activity while maintaining high brain receptor occupancies.
ChemMedChem 10/2012; · 3.15 Impact Factor
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Eric Jnoff, Bernard Christophe,
Philippe Collart,
Francis Coloretti,
Aurel Debeuckelaere,
Marc De Ryck,
Bruno Fuks,
Christophe Genicot,
Michel Gillard,
Michel Guyaux,
Nathalie Price,
Marie-Christine Vandergeten,
Céline Vermeiren
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ABSTRACT: Something to ease the pain: Chemical modification of a 2-amino-oxazoline scaffold led to the identification of α(2C) adrenergic receptor (AR) agonists. These ligands were characterized by a dual α(2C) -AR agonist/α(2A) -AR antagonist profile. Structure-activity relationships were studied, and screening in anesthetized rats demonstrated a superior margin of safety for this class of compounds with respect to cardiovascular effects compared with nonselective α(2) -AR agonists.
ChemMedChem 03/2012; 7(3):385-90. · 3.15 Impact Factor
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Frédéric Denonne,
Sylvain Célanire, Bernard Christophe,
Sabine Defays,
Christel Delaunoy,
Marie-Laure Delporte,
Eric Detrait,
Véronique Durieu,
Michel Gillard,
Yves Lamberty,
Geneviève Lorent,
Jean-Marie Nicolas,
Alain Vanbellinghen,
Nathalie Van Houtvin,
Laurent Provins
ChemMedChem 07/2011; 6(9):1559-65. · 3.15 Impact Factor
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Frédéric Denonne,
Franck Atienzar,
Sylvain Célanire, Bernard Christophe,
Frédérique Delannois,
Christel Delaunoy,
Marie-Laure Delporte,
Véronique Durieu,
Michel Gillard,
Bénédicte Lallemand,
Yves Lamberty,
Geneviève Lorent,
Alain Vanbellinghen,
Nathalie Van Houtvin,
Valérie Verbois,
Laurent Provins
ChemMedChem 02/2010; 5(2):206-12. · 3.15 Impact Factor
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Sylvain Célanire,
Maikel Wijtmans, Bernard Christophe,
Philippe Collart,
Iwan de Esch,
Donald Dassesse,
Christel Delaunoy,
Frédéric Denonne,
Véronique Durieu,
Edith Gelens, [......],
Jean-Marie Nicolas,
Luc Quéré,
Erwin Snip,
Alain Vanbellinghen,
Nathalie Van Houtvin,
Valérie Verbois,
Henk Timmerman,
Patrice Talaga,
Rob Leurs,
Laurent Provins
[show abstract]
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ABSTRACT: H(3)R inverse agonists based on an aminopropoxy-phenyloxazoline framework constitute highly valuable druglike lead compounds that display efficacy in a mouse model of recognition memory.
ChemMedChem 05/2009; 4(7):1063-8. · 3.15 Impact Factor
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Maikel Wijtmans,
Sylvain Celanire,
Erwin Snip,
Michel R Gillard,
Edith Gelens,
Philippe P Collart,
Bastiaan J Venhuis, Bernard Christophe,
Saskia Hulscher,
Henk van der Goot,
Florence Lebon,
Henk Timmerman,
Remko A Bakker,
Bénédicte I L F Lallemand,
Rob Leurs,
Patrice E Talaga,
Iwan J P de Esch
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ABSTRACT: 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.
Journal of Medicinal Chemistry 06/2008; 51(10):2944-53. · 5.25 Impact Factor
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ABSTRACT: SAR around alkyne-quinuclidine derivatives allowed the discovery of highly potent muscarinic antagonists displaying interesting preferential slow off-rates from the M3 receptor.
Bioorganic & medicinal chemistry letters 05/2008; 18(8):2675-8. · 2.65 Impact Factor
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ABSTRACT: Introduction of 3-substituted azetidinyl substituents onto the 4,6-diaminopyrimidine scaffold allowed the improvement of PDE4 inhibiting activities. Preliminary in vivo activity in pulmonary inflammation models is reported.
Bioorganic & Medicinal Chemistry Letters 06/2007; 17(11):3077-80. · 2.55 Impact Factor
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ABSTRACT: SAR around 4,6-diaminopyrimidine derivatives allowed the discovery of the first potent dual M(3) antagonists and PDE4 inhibitors. Various chemical modulations around that scaffold led to the discovery of ucb-101333-3 which is characterized by the most interesting profile on both targets.
Bioorganic & Medicinal Chemistry Letters 05/2006; 16(7):1834-9. · 2.55 Impact Factor
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Jean-Philippe Starck,
Patrice Talaga,
Luc Quéré,
Philippe Collart, Bernard Christophe,
Patrick Lo Brutto,
Sophie Jadot,
Dinesh Chimmanamada,
Matteo Zanda,
Alain Wagner,
Charles Mioskowski,
Roy Massingham,
Michel Guyaux
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ABSTRACT: The synthesis and biological evaluation of a novel family of M(3) muscarinic antagonists are described. A systematic modification of the substituents to a novel alkyne-quinuclidine scaffold yielded original compounds displaying potent in vitro anticholinergic properties.
Bioorganic & Medicinal Chemistry Letters 02/2006; 16(2):373-7. · 2.55 Impact Factor
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Ruengwit Kitbunnadaj,
Obbe P Zuiderveld, Bernard Christophe,
Saskia Hulscher,
Wiro M P B Menge,
Edith Gelens,
Erwin Snip,
Remko A Bakker,
Sylvain Celanire,
Michel Gillard,
Patrice Talaga,
Henk Timmerman,
Rob Leurs
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ABSTRACT: In this study, the piperidine ring of immepip and its analogues was replaced by a rigid heterocyclic pyridine ring. Many compounds in the series exhibit high affinity and agonist activity at the human histamine H(3) receptor. Particularly, the 4-pyridinyl analogue of immepip (1c, immethridine) is identified as a novel potent and highly selective histamine H(3) receptor agonist (pK(i) = 9.07, pEC(50) = 9.74) with a 300-fold selectivity over the closely related H(4) receptor.
Journal of Medicinal Chemistry 06/2004; 47(10):2414-7. · 5.25 Impact Factor
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ABSTRACT: We characterised histamine H(1) receptor antagonism by cetirizine and its enantiomers on isolated guinea pig ileum and trachea. Competitive or mixed (competitive and apparent noncompetitive) antagonism profiles were observed. The order of potency was: chlorpheniramine> or =mepyramine>levocetirizine>cetirizine> or =terfenadine>loratadine>dextrocetirizine. The inhibitory effects of cetirizine, levocetirizine, terfenadine and loratadine were slowly reversible compared to those of dextrocetirizine or mepyramine. Cetirizine and its enantiomers were inactive on L-type Ca(2+) channels. Reduction of the histamine H(1) receptor reserve by dibenamine in the ileum (100-fold higher than in the trachea) showed a gradual change from the competitive profile of dextrocetirizine and mepyramine to a mixed profile. The present results show that cetirizine and levocetirizine are selective competitive but slowly reversible histamine H(1) receptor antagonists. Their mixed antagonism profile observed in the trachea can be explained by the small receptor reserve present in this tissue compared to the ileum and their very slow dissociation rate from the histamine H(1) receptor.
European Journal of Pharmacology 06/2003; 470(1-2):87-94. · 2.52 Impact Factor
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ABSTRACT: In this study, SR 33805 was shown to inhibit competitively [3H]fantofarone binding to cardiac sarcolemmal membranes. In contrast, SR 33805 was shown to inhibit allosterically [3H](+)-PN200-110, [3H](−)-D888 and cis-(+)-[3H]diltiazem binding. In isolated rabbit atrial preparations, SR 33805 was shown to be the least potent of fantofarone, nifedipine, verapamil and diltiazem in terms of both negative chronotropic and inotropic responses (IC50's 6 and 12 μM, respectively). In superfused rat aortic strips, SR 33805 like other Ca2+ channel antagonists, caused a significant inhibition of both K+-induced 45Ca2+ influx and contractile responses. In addition this agent was shown to antagonize Ca2+-induced contractions in K+-depolarized aorta with a pA2 value of 8.39±0.02. In femoral, renal and basilar arteries, SR 33805 was equiactive to the other Ca2+ channel antagonists studied in antagonizing K+-induced contractions (IC50 ∼ 40 nM), but unlike the reference Ca2+ channel antagonists, was equiactive in antagonizing serotonin-induced contractions (IC50 ∼ 250 nM). This suggests that the effects of SR 33805 depend mainly on membrane potential. In conclusion, SR 33805 is a potent Ca2+ channel antagonist which, unlike fantofarone, verapamil and diltiazem, is highly selective for vascular smooth muscle and devoid of any potent negative inotropic actions.
European Journal of Pharmacology: Molecular Pharmacology.
