The role of the 4''-hydroxyl on motilin agonist potency in the 9-dihydroerythromycin series

Yaoquan Liu; Christopher W Carreras; Mark Claypool; David C Myles; Simon J Shaw

doi:10.1016/j.bmcl.2011.04.078

The role of the 4''-hydroxyl on motilin agonist potency in the 9-dihydroerythromycin series

Bioorg Med Chem Lett. 2011 Jun 15;21(12):3712-4. doi: 10.1016/j.bmcl.2011.04.078. Epub 2011 Apr 24.

Authors

Yaoquan Liu¹, Christopher W Carreras, Mark Claypool, David C Myles, Simon J Shaw

Affiliation

¹ Department of Chemistry, Kosan Biosciences, Inc., Hayward, California 94545, USA.

PMID: 21570844
DOI: 10.1016/j.bmcl.2011.04.078

Abstract

The role of the erythromycin 4''-hydroxyl group has been explored on the motilin agonist potential in the 9-dihydroerythromycin series of motilides. The compounds show potencies 2- to 4-fold superior to the corresponding hydroxylated compounds. The relationship is maintained when the 9-hydroxyl is alkylated to generate the corresponding 4''-deoxy-9-O-acetamido-9-dihydroerythromycins. However, concomitant with this increase in potency is an increase in hERG inhibition.

MeSH terms

Cells, Cultured
ERG1 Potassium Channel
Erythromycin / chemistry*
Erythromycin / pharmacology*
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
Gastrointestinal Agents / chemistry
Gastrointestinal Agents / pharmacology
Humans
Hydroxyl Radical* / chemistry
Hydroxyl Radical* / pharmacology
Inhibitory Concentration 50
Molecular Structure
Motilin / agonists*

Substances

ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels
Gastrointestinal Agents
KCNH2 protein, human
Hydroxyl Radical
Motilin
Erythromycin