Potent and orally active non-peptide antagonists of the human melanocortin-4 receptor based on a series of trans-2-disubstituted cyclohexylpiperazines
| Autor: | Dragan Marinkovic, Val S. Goodfellow, Stacy Markison, Jessica Parker, Alan C. Foster, Joseph Pontillo, L. Melissa Arellano, Beth A. Fleck, Nicole S. White, Margaret Joppa, Wanlong Jiang, Joe A. Tran, Caroline W. Chen, Kathleen Gogas, Fabio C. Tucci, Ajay Madan, Chen Chen, John Saunders, Brian Dyck |
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| Rok vydání: | 2005 |
| Předmět: |
medicine.medical_specialty
Cachexia G protein Clinical Biochemistry Administration Oral Biological Availability Pharmaceutical Science Biochemistry Piperazines Energy homeostasis Eating Structure-Activity Relationship Oral administration Internal medicine Drug Discovery medicine Animals Humans Receptor Molecular Biology G protein-coupled receptor Chemistry Organic Chemistry Antagonist Rats Bioavailability Melanocortin 4 receptor Endocrinology Receptor Melanocortin Type 4 Molecular Medicine Protein Binding |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 15:4389-4395 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2005.06.071 |
| Popis: | The melanocortin-4 receptor (MC4R) plays an important role in the regulation of energy homeostasis. Recent studies have shown that blockade of the MC4R reverses tumor-induced weight loss in mice. Herein, we describe the synthesis and identification of potent and selective non-peptide antagonists of the human MC4R from a series of 2-ethoxycarbonylcyclohexyl-piperazines. Compound 12i was found to possess low nanomolar affinity for the MC4R, and exhibit oral bioavailability in rats. More importantly, when administered orally to mice (10 mg/kg), it led to statistically significant increases in food intake over a 24-h period. |
| Databáze: | OpenAIRE |
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