Integration of optimized substituent patterns to produce highly potent 4-aryl-pyridine glucagon receptor antagonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 12; no. 23; pp. 3421 - 3424
• Main Authors: Ladouceur, Gaetan H., Cook, James H., Hertzog, Donald L., Jones, J.Howard, Hundertmark, Thomas, Korpusik, Mary, Lease, Timothy G., Livingston, James N., MacDougall, Margit L., Osterhout, Martin H., Phelan, Kathleen, Romero, Romulo H., Schoen, William R., Shao, Chunning, Smith, Roger A.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 02.12.2002; Elsevier
• Subjects: Benzyl Compounds - chemistry; Benzyl Compounds - pharmacology; Biological and medical sciences; General and cellular metabolism. Vitamins; Inhibitory Concentration 50; Medical sciences; Pharmacology. Drug treatments; Pyridines - chemistry; Pyridines - pharmacology; Receptors, Glucagon - antagonists & inhibitors; Stereoisomerism; Structure-Activity Relationship; Pancreatic hormone; Glucagon; Halophenols; Nitrogen heterocycle; Peptide hormone; Non peptide compound; Non insulin dependent diabetes; In vitro; Pyridine derivatives; Hypoglycemic agent; Structure activity relation; Phenols; Peptidergic receptor; Benzenic compound; Antagonist; Fluorine Organic compounds; Chemical synthesis; Diastereomer
• DOI: 10.1016/S0960-894X(02)00736-9
• ISSN: 0960-894X

Optimized substituent patterns in 4-aryl-pyridine glucagon receptor antagonists were merged to produce highly potent derivatives containing both a 3-[(1 R)-hydroxyethyl] and a 2′-hydroxy group. Due to restricted rotation of the phenyl–pyridine bond, these analogues exist as four isomers. A diastereoselective methylcopper reaction was developed to facilitate the synthesis, and single isomers were isolated with activities in the range IC 50=10–25 nM. Optimized substituent patterns in 4-aryl-pyridine glucagon receptor antagonists were merged to produce highly potent derivatives containing both a 3-[(1 R)-hydroxyethyl] and a 2′-hydroxy group. Due to restricted rotation of the phenyl–pyridine bond, these analogues exist as four isomers. A diastereoselective methylcopper reaction was developed to facilitate the synthesis, and single isomers were isolated with activities in the range IC 50=10–25 nM.