9-Dihydroerythromycin ethers as motilin agonists--developing structure-activity relationships for potency and safety.
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.
Liu
Yaoquan
Y
Department of Chemistry, Kosan Biosciences, Inc., 3832 Bay Center Place, Hayward, CA 94545, USA.
Li
Yong
Y
Myles
David C
DC
Claypool
Mark
M
Carreras
Christopher W
CW
Shaw
Simon J
SJ
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
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