Novel and highly potent histamine H3 receptor ligands. Part 1: withdrawing of hERG activity

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 18; pp. 5378 - 5383
• Main Authors: Levoin, Nicolas, Labeeuw, Olivier, Calmels, Thierry, Poupardin-Olivier, Olivia, Berrebi-Bertrand, Isabelle, Lecomte, Jeanne-Marie, Schwartz, Jean-Charles, Capet, Marc
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.09.2011; Elsevier
• Subjects: antagonists; Binding Sites - drug effects; Biological and medical sciences; Dose-Response Relationship, Drug; Ethers - chemical synthesis; Ethers - chemistry; Ethers - pharmacology; H3R; HERG; Histamine; Histamine H3 Antagonists - chemical synthesis; Histamine H3 Antagonists - chemistry; Histamine H3 Antagonists - pharmacology; Humans; Ligands; Medical sciences; Miscellaneous; Models, Molecular; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; QSAR; Quantitative Structure-Activity Relationship; quantitative structure-activity relationships; receptors; Stereoisomerism; Trans-Activators - antagonists & inhibitors; Trans-Activators - metabolism; Transcriptional Regulator ERG; Histamine; HERG; QSAR; H3R; H3 histamine receptor; Toxicity; Benzene derivatives; Prediction; Aminoether; Ionic channel; Structure activity relation; Piperidine derivatives; Affinity; Property structure relationship; Antagonist; Circulatory system; Chemical synthesis; Lipophilicity; Physicochemical properties
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.07.006

Pre-clinical investigation of some aryl-piperidinyl ether histamine H3 receptor antagonists revealed a strong hERG binding. To overcome this issue, we have developed a QSAR model specially dedicated to H3 receptor ligands. This model was designed to be directly applicable in medicinal chemistry with no need of molecular modeling. The resulting recursive partitioning trees are robust (80–85% accuracy), but also simple and comprehensible. A novel promising lead emerged from our work and the structure–activity relationships are presented.