title: Discovery of agonists of cannabinoid receptor 1 with restricted central nervous system penetration aimed for treatment of gastroesophageal reflux disease.
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.
authors.affiliation: AstraZeneca Research and Development, Pepparedsleden 1, Mölndal 43183, Sweden. alleyn.plowright@astrazeneca.com
authors.forename: Alleyn T
authors.initials: AT
authors.lastname: Plowright
authors.forename: Karolina
authors.initials: K
authors.lastname: Nilsson
authors.forename: Madeleine
authors.initials: M
authors.lastname: Antonsson
authors.forename: Kosrat
authors.initials: K
authors.lastname: Amin
authors.forename: Johan
authors.initials: J
authors.lastname: Broddefalk
authors.forename: Jörgen
authors.initials: J
authors.lastname: Jensen
authors.forename: Anders
authors.initials: A
authors.lastname: Lehmann
authors.forename: Shujuan
authors.initials: S
authors.lastname: Jin
authors.forename: Stephane
authors.initials: S
authors.lastname: St-Onge
authors.forename: Mirosław J
authors.initials: MJ
authors.lastname: Tomaszewski
authors.forename: Maxime
authors.initials: M
authors.lastname: Tremblay
authors.forename: Christopher
authors.initials: C
authors.lastname: Walpole
authors.forename: Zhongyong
authors.initials: Z
authors.lastname: Wei
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.forename: Johan
authors.initials: J
authors.lastname: Ulander
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D001549:Benzamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004285:Dogs; D000072237:ERG1 Potassium Channel; D049630:Esophageal Sphincter, Lower / Q000187:drug effects / Q000502:physiology; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005764:Gastroesophageal Reflux / Q000188:drug therapy*; D057166:High-Throughput Screening Assays; D006801:Humans; D009126:Muscle Relaxation / Q000187:drug effects; D011719:Pyrazines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D012995:Solubility; D013329:Structure-Activity Relationship; D013454:Sulfoxides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D001549:Benzamides; D065692:Cytochrome P-450 CYP3A Inhibitors; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D011719:Pyrazines; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D013454:Sulfoxides; D014230:Triazoles; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human