title: Discovery and optimization of 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivatives as a novel class of selective cannabinoid CB2 receptor agonists.
abstract: Here, we report the identification and optimization of 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivatives as a novel chemotype with selective cannabinoid CB2 receptor agonist activity. 1 is a potent and selective cannabinoid CB2 receptor agonist (hCB2 pEC(50) = 8.6). The compound was found to be metabolically unstable, which resulted in low oral bioavailability in rat (F(po) = 4%) and possessed off-target activity at the hERG ion channel (pK(i) = 5.5). Systematic modification of physicochemical properties, such as lipophilicity and basicity, was used to optimize the pharmacokinetic profile and hERG affinity of this novel class of cannabinoid CB2 receptor agonists. This led to the identification of 44 as a potent, selective, and orally bioavailable cannabinoid CB2 receptor agonist (hCB2 pEC(50) = 8.0; hERG pK(i) < 4; F(po) = 100%), which was active in a rat spinal nerve ligation model of neuropathic pain.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Oss, The Netherlands. mario.vanderstelt@ntrc.nl
authors.forename: Mario
authors.initials: M
authors.lastname: van der Stelt
authors.forename: Jos
authors.initials: J
authors.lastname: Cals
authors.forename: Silvia
authors.initials: S
authors.lastname: Broeders-Josten
authors.forename: Jean
authors.initials: J
authors.lastname: Cottney
authors.forename: Antoon A
authors.initials: AA
authors.lastname: van der Doelen
authors.forename: Marcel
authors.initials: M
authors.lastname: Hermkens
authors.forename: Vera
authors.initials: V
authors.lastname: de Kimpe
authors.forename: Angela
authors.initials: A
authors.lastname: King
authors.forename: Jan
authors.initials: J
authors.lastname: Klomp
authors.forename: Julia
authors.initials: J
authors.lastname: Oosterom
authors.forename: Ilse
authors.initials: I
authors.lastname: Pols-de Rooij
authors.forename: Jeroen
authors.initials: J
authors.lastname: de Roos
authors.forename: Martin
authors.initials: M
authors.lastname: van Tilborg
authors.forename: Susan
authors.initials: S
authors.lastname: Boyce
authors.forename: James
authors.initials: J
authors.lastname: Baker
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009437:Neuralgia / Q000188:drug therapy / Q000209:etiology; D051381:Rats; D017208:Rats, Wistar; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D013127:Spinal Nerves / Q000293:injuries; D013329:Structure-Activity Relationship
chemical_list: C568963:3-cyclopropyl-1-(4-(6-(1,1-dioxo-1gamma6-thiomorpholin-4-ylmethyl)-5-fluoro-pyridin-2-yl)benzyl)imidazolidine-2,4-dione; D000700:Analgesics; D003499:Cyclic S-Oxides; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006827:Hydantoins; C000606913:KCNH2 protein, human; D043885:Receptor, Cannabinoid, CB2; D000242:Cyclic AMP