1. Discovery of agonists of cannabinoid receptor 1 with restricted central nervous system penetration aimed for treatment of gastroesophageal reflux disease.
- Author
-
Plowright AT, Nilsson K, Antonsson M, Amin K, Broddefalk J, Jensen J, Lehmann A, Jin S, St-Onge S, Tomaszewski MJ, Tremblay M, Walpole C, Wei Z, Yang H, and Ulander J
- Subjects
- Administration, Oral, Animals, Aryl Hydrocarbon Hydroxylases antagonists & inhibitors, Benzamides pharmacokinetics, Benzamides pharmacology, Biological Availability, Cell Line, Cricetinae, Cricetulus, Cytochrome P-450 CYP2C9, Cytochrome P-450 CYP3A, Cytochrome P-450 CYP3A Inhibitors, Dogs, ERG1 Potassium Channel, Esophageal Sphincter, Lower drug effects, Esophageal Sphincter, Lower physiology, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, High-Throughput Screening Assays, Humans, Muscle Relaxation drug effects, Pyrazines chemical synthesis, Pyrazines pharmacokinetics, Pyrazines pharmacology, Pyridines chemical synthesis, Pyridines pharmacokinetics, Pyridines pharmacology, Radioligand Assay, Rats, Rats, Sprague-Dawley, Solubility, Structure-Activity Relationship, Sulfoxides chemical synthesis, Sulfoxides pharmacokinetics, Sulfoxides pharmacology, Triazoles chemical synthesis, Triazoles pharmacokinetics, Triazoles pharmacology, Benzamides chemical synthesis, Brain metabolism, Gastroesophageal Reflux drug therapy, Receptor, Cannabinoid, CB1 agonists
- Abstract
Agonists of the cannabinoid receptor 1 (CB1) have been suggested as possible treatments for a range of medical disorders including gastroesophageal reflux disease (GERD). While centrally acting cannabinoid agonists are known to produce psychotropic effects, it has been suggested that the CB1 receptors in the periphery could play a significant role in reducing reflux. A moderately potent and highly lipophilic series of 2-aminobenzamides was identified through focused screening of GPCR libraries. Development of this series focused on improving potency and efficacy at the CB1 receptor, reducing lipophilicity and limiting the central nervous system (CNS) exposure while maintaining good oral absorption. Improvement of the series led to compounds having excellent potency at the CB1 receptor and high levels of agonism, good physical and pharmacokinetic properties, and low penetration into the CNS. A range of compounds demonstrated a dose-dependent inhibition of transient lower esophageal sphincter relaxations in a dog model.
- Published
- 2013
- Full Text
- View/download PDF