Bernard Christophe

Peripheral and central H1 histamine receptor occupancy by levocetirizine, a non‐sedating antihistamine; a time course study in the guinea pig

The H1 receptor occupancy (H1RO) in brain is an indicator of central side effects of antihistamines. Here, we determined the kinetics of central and peripheral H1RO by levocetirizine in relation to its brain and plasma concentration, and investigated the role of the blood‐brain barrier in any delay in brain H1RO.

Histamine H1 receptor antagonism by cetirizine in isolated guinea pig tissues: influence of receptor reserve and dissociation kinetics

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.

4-Benzyl-1H-imidazoles with Oxazoline Termini as Histamine H3 Receptor Agonists

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.

In vitro characterization of a novel Ca2+ entry blocker: SR 33805.

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 (IC50s 6 and 12 microM, 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 Ca(2+)-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 approximately 40 nM), but unlike the reference Ca2+ channel antagonists, was equiactive in antagonizing serotonin-induced contractions (IC50 approximately 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.

Phenyl-oxazoles, a New Family of Inverse Agonists at the H3 Histamine Receptor

Biogenic amines, such as histamine, are very important in human physiology. In particular, histamine is implicated in allergy (H1 receptor), [1] gastric secretion (H2R), [2] sleep/wake cycles or cognition (H3R) [3] and inflammatory/immunological processes (H4R). [4] The cloning and characterisation of H3R [5] have allowed many pharmaceutical companies to run highthroughput screening (HTS) campaigns and successfully come up with drug candidates. Pfizer, Sanofi-Aventis and Cephalon all currently have a compound in phase I clinical trials (PF3654746, SAR-110894, and CEP-26401 for Alzheimer’s disease). Moreover GlaxoSmithKline, Johnson & Johnson, Bioprojet, Transtech and Schering-Plough each have a compound in phase II (GSK-239512, BF2.649 and JNJ-31001074 as cognition enhancers, 9] SCH-497079 and HPP-404 against obesity, and BF2.649 for schizophrenia). A phase II study on another compound, GSK-189254, for the treatment of narcolepsy has recently been terminated. Several other candidates are in preclinical development or have reached some point in development for which results are expected in the near future.

Discovery of a new class of non-imidazole oxazoline-based histamine H(3) receptor (H(3)R) inverse agonists

H3R inverse agonists based on an aminopropoxy‐phenyloxazoline framework constitute highly valuable druglike lead compounds that display efficacy in a mouse model of recognition memory.

A new series of M3 muscarinic antagonists based on the 4-amino-piperidine scaffold

A series of 4-amino-piperidine containing molecules have been synthesized and structure-affinity relationship toward the M3-muscarinic receptor has been investigated. Chemical modulations provided molecules with K(i) for the human M3-R up to 1 nM with variable selectivity (3- to 40-fold) over the human M2-R. Compounds 2 (pA(2)=8.3, 8.6) demonstrates in vitro on guinea pig bladder and ileal strips potent anticholinergic properties and tissue selectivity.

Alkyne–quinuclidine derivatives as potent and selective muscarinic antagonists for the treatment of COPD

SAR around alkyne-quinuclidine derivatives allowed the discovery of highly potent muscarinic antagonists displaying interesting preferential slow off-rates from the M3 receptor.

Discovery of orally bioavailable NK1 receptor antagonists

Benzyloxyphenethylpiperazines are a new class of high affinity NK1 receptor antagonists. Oral bioavailability and selectivity can be fine tuned by the nature of the substituents on the basic nitrogen atom. Addition of substituents with a carboxylic acid group led to very selective and orally active NK1 antagonists free of interaction with L-type calcium channels.

Acetamide Scanning around Bicyclic Thiazoles: SAR at the H3 Receptor

The third histamine receptor (H3R) is expressed mainly in the central nervous system (CNS) and regulates the release of numerous other neurotransmitters. It is highly interesting as a target for the control of CNS disorders such as excessive daytime sleepiness and cognitive disorders such as Alzheimer’s disease. In our medicinal chemistry investigations around this receptor, we have identified nanomolar-affinity ligands based on a phenyloxazole scaffold (Figure 1). We noticed that affinity increased between isomers I and II. Starting from thiazole III, we embarked on a systematic comparison of rigid bicyclic thiazoles bearing the N-acetyl side chain in all orientations in an attempt to identify the isomer with the best properties. This isomer was then used to further explore the structure– activity relationships (SAR).