3-Benzhydryl-4-piperidones as novel neurokinin-1 receptor antagonists and their efficient synthesis

• Published in: Bioorganic & medicinal chemistry 2011-09, Vol.19 (17), p.5175-5182
• Main Authors: Shirai, Junya, Nakamura, Minoru, Tarui, Naoki, Hashimoto, Tadatoshi, Ikeura, Yoshinori
• Format: Article
• Language: English
• Subjects: alcohols; antagonists; Biological and medical sciences; bromides; Cell Line; condensation; G-protein coupled receptors; Humans; Medical sciences; Neurokinin-1 Receptor Antagonists; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Piperidones - chemical synthesis; Piperidones - chemistry; Piperidones - pharmacology; Protein Binding; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, G-Protein-Coupled - metabolism; Receptors, Neurokinin-1 - metabolism; skeleton; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.07.014

A series of novel 3-benzhydryl-4-piperidone derivatives were identified as potent tachykinin neurokinin-1 (NK₁) receptor antagonists. An efficient and versatile synthesis of this series was achieved with a coupling reaction of 1-benzylpiperidones with benzhydryl bromides or benzhydrols in the presence of trifluoromethanesulfonate and a condensation reaction of piperidones with benzyl alcohols using ethyl o-phenylenephosphate. The 3-benzhydryl-4-piperidone skeleton, which has a 1,1-diphenylmethane moiety that is a known privileged substructure targeting G-protein coupled receptors, can be used for chemical library synthesis because of chemical accessibility and diversity.