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.
MeSH terms
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Administration, Oral
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Animals
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Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors
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Benzamides / chemical synthesis*
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Benzamides / pharmacokinetics
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Benzamides / pharmacology
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Biological Availability
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Brain / metabolism*
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Cell Line
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Cricetinae
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Cricetulus
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Cytochrome P-450 CYP2C9
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Cytochrome P-450 CYP3A
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Cytochrome P-450 CYP3A Inhibitors
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Dogs
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ERG1 Potassium Channel
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Esophageal Sphincter, Lower / drug effects
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Esophageal Sphincter, Lower / physiology
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
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Gastroesophageal Reflux / drug therapy*
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High-Throughput Screening Assays
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Humans
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Muscle Relaxation / drug effects
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Pyrazines / chemical synthesis
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Pyrazines / pharmacokinetics
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Pyrazines / pharmacology
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Pyridines / chemical synthesis
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Pyridines / pharmacokinetics
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Pyridines / pharmacology
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Radioligand Assay
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Rats
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Rats, Sprague-Dawley
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Receptor, Cannabinoid, CB1 / agonists*
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Solubility
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Structure-Activity Relationship
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Sulfoxides / chemical synthesis
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Sulfoxides / pharmacokinetics
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Sulfoxides / pharmacology
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Triazoles / chemical synthesis
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Triazoles / pharmacokinetics
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Triazoles / pharmacology
Substances
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Benzamides
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Cytochrome P-450 CYP3A Inhibitors
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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Pyrazines
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Pyridines
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Receptor, Cannabinoid, CB1
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Sulfoxides
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Triazoles
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CYP2C9 protein, human
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Cytochrome P-450 CYP2C9
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Aryl Hydrocarbon Hydroxylases
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human