title: Structure-activity relationships of 9-substituted-9-dihydroerythromycin-based motilin agonists: optimizing for potency and safety.
abstract: A series of 9-dihydro-9-acetamido-N-desmethyl-N-isopropyl erythromycin A analogues and related derivatives was generated as motilin agonists. The compounds were optimized for potency while showing both minimal antibacterial activity and hERG inhibition. As the substituent on the amide was increased in lipophilicity the potency and hERG inhibition increased, while polar groups lowered potency, without significantly impacting hERG inhibition. The N-methyl acetamide 7a showed the optimal in vitro profile and was probed further by varying the chain length to the macrocycle as well as changing the macrocycle scaffold. 7a remained the compound with the best in vitro properties.
authors.affiliation: Department of Chemistry, Kosan Biosciences, Inc., Hayward, California 94545, USA. sshaw@rigel.com
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Shaw
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
authors.forename: Hao
authors.initials: H
authors.lastname: Zheng
authors.forename: Hong
authors.initials: H
authors.lastname: Fu
authors.forename: Mark A
authors.initials: MA
authors.lastname: Burlingame
authors.forename: Saul
authors.initials: S
authors.lastname: Marquez
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Mark
authors.initials: M
authors.lastname: Claypool
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Carreras
authors.forename: William
authors.initials: W
authors.lastname: Crumb
authors.forename: Dwight J
authors.initials: DJ
authors.lastname: Hardy
authors.forename: David C
authors.initials: DC
authors.lastname: Myles
authors.forename: Yaoquan
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D001419:Bacteria / Q000187:drug effects / Q000302:isolation & purification; D002460:Cell Line; D000072237:ERG1 Potassium Channel; D004917:Erythromycin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005765:Gastrointestinal Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007422:Intestines / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D009037:Motilin / Q000819:agonists*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013618:Tachyphylaxis
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005765:Gastrointestinal Agents; C000606913:KCNH2 protein, human; D009037:Motilin; D004917:Erythromycin