Sylvain Celanire

Keynote review: histamine H3 receptor antagonists reach out for the clinic

Antagonists of the histamine H(1) and H(2) receptors have been successful as blockbuster drugs for treating allergic conditions and gastric ulcers, respectively. As such, histamine receptors have made a significant contribution to establishing G-Protein-coupled receptors as the favored drug targets of the industry. In this light, it can easily be understood that the discovery of a third histamine receptor subtype (H(3)R) in 1983 was greeted with considerable excitement. However, characterization of the H(3)R turned out to be far from trivial. In the past five years, molecular biology approaches have given fresh impetus to the H(3)R research field. As a result, H(3)R ligands are where they were anticipated to be 20 years ago: at the center of attention and on the verge of an anticipated breakthrough as the next generation of histaminergic blockbuster drugs. Here, we assess the status of the H(3)R medicinal chemistry programs of the various players in the field, as far as can be deduced from patent applications and scientific literature.

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.

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.

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).

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

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.

Lead Optimization of Thiazolo[5,4-c]piperidines: 3-Cyclobutoxy Linker as a Key Spacer for H3R Inverse Agonists

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.