Melanocortin subtype-4 receptor agonists containing a piperazine core with substituted aryl sulfonamides

• Published in: Bioorganic & medicinal chemistry letters Vol. 15; no. 6; pp. 1623 - 1627
• Main Authors: Fotsch, Christopher, Han, Nianhe, Arasasingham, Premilla, Bo, Yunxin, Carmouche, Michelle, Chen, Ning, Davis, James, Goldberg, Martin H., Hale, Clarence, Hsieh, Feng-Yin, Kelly, Michael G., Liu, Qingyian, Norman, Mark H., Smith, Duncan M., Stec, Markian, Tamayo, Nuria, Xi, Ning, Xu, Shimin, Bannon, Anthony W., Baumgartner, James W.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.03.2005; Elsevier
• Subjects: Animals; Binding, Competitive; Biological and medical sciences; Feeding; Feeding Behavior - drug effects; Humans; In Vitro Techniques; Male; Medical sciences; Melanocortin subtype 4 receptor; Mice; Mice, Inbred C57BL; Miscellaneous; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Piperazine; Piperazines - chemistry; Piperazines - pharmacology; Protein Binding; Receptor, Melanocortin, Type 4 - agonists; Structure-Activity Relationship; Sulfonamides - chemistry; Sulfonamides - pharmacology; Piperazine; Melanocortin subtype 4 receptor; Feeding; Agonist; Isoquinoline derivatives; Sulfonamide; Peptides; Rodentia; Oral administration; Selectivity; Vertebrata; Mammalia; Structure activity relation; MC4 melanocortin receptor; Mouse; Food intake; Chlorine Organic compounds; Animal; Dipeptides; Anorectic; Piperazine derivatives; Pharmacokinetics; Chemical synthesis; Biological receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.01.060

The biological activity for a set of melanocortin-4 receptor (MC4R) agonists containing a piperazine core with an ortho-substituted aryl sulfonamide is described. Compounds from this set had binding and functional activities at MC4R less than 30 nM. The most selective compound in this series was >25,000-fold more potent at MC4R than MC3R, and 490-fold more potent at MC4R than MC5R. This compound also reduced food intake after oral dosing at 25, 50, and 100 mg kg −1 in fasted mice. The biological activity for a set of melanocortin-4 receptor (MC4R) agonists containing a piperazine core with an ortho-substituted aryl sulfonamide is described. Compounds from this set had binding and functional activities at MC4R less than 30 nM. The most selective compound in this series was >25,000-fold more potent at MC4R than MC3R, and 490-fold more potent at MC4R than MC5R. This compound also reduced food intake after oral dosing at 25, 50, and 100 mg kg −1 in fasted mice.