title: 9-Dihydroerythromycin ethers as motilin agonists--developing structure-activity relationships for potency and safety.
abstract: A series of derivatives of the amine of 9-dihydro-9-O-ethylamino-N-desmethyl-N-isopropyl erythromycin A derivatives were synthesized as motilin agonists. The compounds were developed for potency without showing antibacterial activity and inhibition of the hERG potassium channel. The formamide of the amide series was found to show the optimal combination of properties relative to carbamates, ureas, thioureas, and amines. This prompted an investigation of heterocyclic isosteres for the amide. In this series the triazole had the optimal combination of properties. From the study, two compounds met the criteria for detailed pharmacokinetic studies.
authors.affiliation: Department of Chemistry, Kosan Biosciences, Inc., 3832 Bay Center Place, Hayward, CA 94545, USA.
authors.forename: Yaoquan
authors.initials: Y
authors.lastname: Liu
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: David C
authors.initials: DC
authors.lastname: Myles
authors.forename: Mark
authors.initials: M
authors.lastname: Claypool
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Carreras
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Shaw
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000072237:ERG1 Potassium Channel; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D009037:Motilin / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D004987:Ethers; C000606913:KCNH2 protein, human; D009037:Motilin; D004917:Erythromycin