Discovery of 1,3-disubstituted-1H-pyrrole derivatives as potent Melanin-Concentrating Hormone Receptor 1 (MCH-R1) antagonists

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 17; pp. 4859 - 4863
• Main Authors: Berglund, Susanne, Egner, Bryan J., Gradén, Henrik, Gradén, Joakim, Morgan, David G.A., Inghardt, Tord, Giordanetto, Fabrizio
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.09.2008; Elsevier
• Subjects: Animals; Anti-Obesity Agents - chemistry; Anti-Obesity Agents - pharmacokinetics; Anti-Obesity Agents - pharmacology; Biological and medical sciences; Drug Stability; Hormones. Endocrine system; Humans; MCH; MCH-R1 antagonists; Medical sciences; Melanin-Concentrating Hormone; Mice; Obesity; Pharmacology. Drug treatments; Pyrroles - chemistry; Pyrroles - pharmacokinetics; Pyrroles - pharmacology; Receptors, Somatostatin - antagonists & inhibitors; Receptors, Somatostatin - metabolism; Structure-Activity Relationship; MCH-R1 antagonists; Obesity; MCH; Melanin-Concentrating Hormone; Intravenous administration; Rodentia; Oral administration; In vitro; Melanin-Concentrating Hormone;MCH;MCH-R1 antagonists;Obesity; Pyrrole derivatives; In vivo; Vertebrata; Mammalia; Structure activity relation; Mouse; Animal; Chlorine Organic compounds; Piperidine derivatives; Melanin concentrating hormone; Carboxamide; Antagonist; Fluorine Organic compounds; Pharmacokinetics; Chemical synthesis; Nutritional status; Biological receptor; Hormonal receptor
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.07.079

The optimization of an HTS-derived hit compound into a potent and metabolically stable MCH-R1 antagonist is described. A series of 1,3-disubstituted-1H-pyrrole-based antagonists of the human Melanin-Concentrating Hormone Receptor 1 (h-MCH-R1) are reported. High-throughput screening of the AstraZeneca compound collection yielded 1, a hit with moderate affinity towards MCH-R1. Subsequent structural manipulations and SAR analysis served to rationalize potency requirements, and 12 was identified as a novel, functional MCH-R1 antagonist with favorable pharmacokinetic properties.