A concise synthesis of 1,4-dihydro-[1,4]diazepine-5,7-dione, a novel 7-TM receptor ligand core structure with melanocortin receptor agonist activity

• Published in: Bioorganic & medicinal chemistry 2010-03, Vol.18 (5), p.1822-1833
• Main Authors: Szewczyk, Jerzy R., Laudeman, Chris P., Sammond, Doug M., Villeneuve, Manon, Minick, Douglas J., Grizzle, Mary K., Daniels, Alejandro J., Andrews, John L., Ignar, Diane M.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Agonist; Animals; Azepines - chemical synthesis; Azepines - chemistry; Azepines - pharmacokinetics; Benzodiazepines - chemistry; Biological and medical sciences; Circular Dichroism; Eating - drug effects; Food intake; G protein-coupled receptors; General and cellular metabolism. Vitamins; Ligands; MC1R; MC4R; Medical sciences; Melanocyte-Stimulating Hormones - chemical synthesis; Melanocyte-Stimulating Hormones - chemistry; Melanocyte-Stimulating Hormones - pharmacokinetics; Peptides - pharmacology; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 1 - agonists; Receptor, Melanocortin, Type 1 - metabolism; Receptor, Melanocortin, Type 4 - agonists; Receptor, Melanocortin, Type 4 - metabolism; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - metabolism; Stereoisomerism; Structure-Activity Relationship; Tetrahydrodiazepine-5,7-dione
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.01.049

Finding small non-peptide molecules for G protein-coupled receptors (GPCR) whose endogenous ligands are peptides, is a very important task for medicinal chemists. Over the years, compounds mimicking peptide structures have been discovered, and scaffolds emulating peptide backbones have been designed. In our work on GPCR ligands, including cholecystokinin receptor-1 (CCKR-1) agonists, we have employed benzodiazepines as a core structure. Looking for ways to reduce molecular weight and possibly improve physical properties of GPCR ligands, we embarked on the search for molecules providing similar scaffolds to the benzodiazepine with lower molecular weight. One of our target core structures was 1,4-dihydro-[1,4]diazepine-5,7-dione. There was not, however, a known synthetic route to such molecules. Here we report the discovery of a simple and concise method for synthesis of 2-[6-(1 H-indazol-3-ylmethyl)-5,7-dioxo-4-phenyl-4,5,6,7-tetrahydro-[1,4]diazepin-1-yl]- N-isopropyl- N-phenyl-acetamide as an example of a compound containing the tetrahydrodiazepine-5,7-dione core. Compounds from this series were tested in numerous GPCR assays and demonstrated activity at melanocortin 1 and 4 receptors (MC1R and MC4R). Selected compounds from this series were tested in vivo in Peptide YY (PYY)-induced food intake. Compounds dosed by intracerebroventricular and oral routes reduced PYY-induced food intake and this effect was reversed by the cyclic peptide MC4R antagonist SHU9119.