Structure−Activity Relationships of a Series of Pyrrolo[3,2-d]pyrimidine Derivatives and Related Compounds as Neuropeptide Y5 Receptor Antagonists

• Published in: Journal of medicinal chemistry Vol. 43; no. 22; pp. 4288 - 4312
• Main Authors: Norman, Mark H, Chen, Ning, Chen, Zhidong, Fotsch, Christopher, Hale, Clarence, Han, Nianhe, Hurt, Ray, Jenkins, Tracy, Kincaid, John, Liu, Longbin, Lu, Yuelie, Moreno, Ofir, Santora, Vincent J, Sonnenberg, Jennifer D, Karbon, William
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 02.11.2000; Amer Chemical Soc
• Subjects: Anti-Obesity Agents - chemical synthesis; Anti-Obesity Agents - chemistry; Anti-Obesity Agents - pharmacology; Biological and medical sciences; Cell Line; Chemistry, Medicinal; Drug Evaluation, Preclinical; Feeding. Feeding behavior; Fundamental and applied biological sciences. Psychology; Humans; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Medical sciences; Membranes - metabolism; Metabolic diseases; Models, Biological; Obesity; Pharmacology & Pharmacy; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Radioligand Assay; Receptors, Neuropeptide Y - antagonists & inhibitors; Receptors, Neuropeptide Y - metabolism; Science & Technology; Structure-Activity Relationship; Vertebrates: anatomy and physiology, studies on body, several organs or systems; TARGETS; OBESITY; SUBTYPES; FOOD-INTAKE; DRUGS; Neuropeptide Y; Obesity; Feeding behavior; Nitrogen heterocycle; Nutrition disorder; In vitro; Structure activity relation; Six membered ring; Piperidine derivatives; Bicyclic compound; Peptidergic receptor; Antagonist; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm000269t

Neuropeptide Y (NPY) has been shown to play an important role in the regulation of food intake and energy balance. Pharmacological data suggests that the Y5 receptor subtype contributes to the effects of NPY on appetite, and therefore a Y5 antagonist might be a useful therapeutic agent for the treatment of obesity. In attempts to identify potential Y5 antagonists, a series of pyrrolo[3,2-d]pyrimidine derivatives was prepared and evaluated for their ability to bind to Y5 receptors in vitro. We report here the synthesis and initial structure−activity relationship investigations for this class of compounds. The target compounds were prepared by a variety of synthetic routes designed to modify both the substitution and the heterocyclic core of the pyrrolo[3,2-d]pyrimidine lead 1. In addition to identifying several potent Y5 antagonists for evaluation as potential antiobesity agents, a pharmacophore model for the human Y5 receptor is presented.