Optimization of the 4-aryl group of 4-aryl-pyridine glucagon antagonists: development of an efficient, alternative synthesis

• Published in: Bioorganic & medicinal chemistry letters Vol. 12; no. 9; pp. 1303 - 1306
• Main Authors: Smith, Roger A., Hertzog, Donald L., Osterhout, Martin H., Ladouceur, Gaetan H., Korpusik, Mary, Bobko, Mark A., Jones, J.Howard, Phelan, Kathleen, Romero, Romulo H., Hundertmark, Thomas, MacDougall, Margit L., Livingston, James N., Schoen, William R.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 06.05.2002; Elsevier
• Subjects: Biological and medical sciences; General and cellular metabolism. Vitamins; Glucagon - antagonists & inhibitors; Medical sciences; Pharmacology. Drug treatments; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Structure-Activity Relationship; Human; Glucagon; Halophenols; Nitrogen heterocycle; Benzene derivatives; Non peptide compound; In vitro; Hypoglycemic agent; Structure activity relation; Six membered ring; Affinity; Fluorine Organic compounds; Antagonist; Chemical synthesis; Biological receptor; Hormonal receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(02)00143-9

A narrow structure–activity relationship was established for the 4-aryl group in 4-aryl-pyridine glucagon antagonists, with only small substituents being well-tolerated, and only at the 3′- and 4′-positions. However, substitution with a 2′-hydroxy group gave a ca. 3-fold increase in activity (e.g., 4′-fluoro-2′-hydroxy analogue 33, IC 50=190 nM). For efficient preparation of 2′-substituted phenylpyridines, a novel synthesis via pyrones and 4-methoxy-pyridines was developed. A narrow structure–activity relationship was established for the 4-aryl group in 4-aryl-pyridine glucagon antagonists. However, substitution with a 2′-hydroxy group gave a ca. 3-fold increase in activity. For efficient preparation of 2′-substituted phenylpyridines, a novel synthesis via pyrones and 4-methoxy-pyridines was developed.