Structure−Activity Relationships of 9-Substituted-9-Dihydroerythromycin-Based Motilin Agonists: Optimizing for Potency and Safety

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2009-11, Vol.52 (21), p.6851-6859
Main Authors: Shaw, Simon J, Chen, Yue, Zheng, Hao, Fu, Hong, Burlingame, Mark A, Marquez, Saul, Li, Yong, Claypool, Mark, Carreras, Christopher W, Crumb, William, Hardy, Dwight J, Myles, David C, Liu, Yaoquan
Format: Article
Language:English
Subjects:
Animals
Antibacterial agents
Antibiotics. Antiinfectious agents. Antiparasitic agents
Bacteria - drug effects
Bacteria - isolation & purification
Biological and medical sciences
Cell Line
ERG1 Potassium Channel
Erythromycin - adverse effects
Erythromycin - analogs & derivatives
Erythromycin - chemical synthesis
Erythromycin - pharmacology
Ether-A-Go-Go Potassium Channels - antagonists & inhibitors
Gastrointestinal Agents - adverse effects
Gastrointestinal Agents - chemical synthesis
Gastrointestinal Agents - pharmacology
Humans
In Vitro Techniques
Intestines - microbiology
Medical sciences
Microbial Sensitivity Tests
Motilin - agonists
Muscle Contraction - drug effects
Muscle, Smooth - drug effects
Muscle, Smooth - physiology
Pharmacology. Drug treatments
Rabbits
Stereoisomerism
Structure-Activity Relationship
Tachyphylaxis
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Description
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm901107f