Arylpropionylpiperazines as antagonists of the human melanocortin-4 receptor

• Published in: Bioorganic & medicinal chemistry letters 2006-09, Vol.16 (17), p.4674-4678
• Main Authors: Jiang, Wanlong, Tucci, Fabio C., Chen, Caroline W., Arellano, Melissa, Tran, Joe A., White, Nicole S., Marinkovic, Dragan, Pontillo, Joseph, Fleck, Beth A., Wen, Jenny, Saunders, John, Madan, Ajay, Foster, Alan C., Chen, Chen
• Format: Article
• Language: English
• Subjects: Animals; Antagonist; Arylpropinylpiperazine, synthesis; Benzylamines - chemistry; Biological and medical sciences; Humans; Medical sciences; Melanocortin; Mice; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacokinetics; Piperazines - pharmacology; Receptor, Melanocortin, Type 4 - antagonists & inhibitors; Receptor, Melanocortin, Type 4 - metabolism; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.05.088

A series of 3-arylpropionylpiperazines were synthesized as antagonists of the melanocortin-4 receptor. Their potency was found to be increased by replacing the α-methyl substituent of the initial lead 11 with a larger s-Bu or i-Bu group. Further potency enhancement was observed when a glycine or β-alanine was incorporated onto the benzylamine. Some compounds demonstrated good potency, moderate selectivity, and oral bioavailability.