Structure-activity relationships of 9-substituted-9-dihydroerythromycin-based motilin agonists: optimizing for potency and safety.

Article Details

Citation

Copy to clipboard

Shaw SJ, Chen Y, Zheng H, Fu H, Burlingame MA, Marquez S, Li Y, Claypool M, Carreras CW, Crumb W, Hardy DJ, Myles DC, Liu Y

Structure-activity relationships of 9-substituted-9-dihydroerythromycin-based motilin agonists: optimizing for potency and safety.

J Med Chem. 2009 Nov 12;52(21):6851-9. doi: 10.1021/jm901107f.

PubMed ID

19821563 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Erythromycin	Potassium voltage-gated channel subfamily H member 2	IC 50 (nM)	39	N/A	N/A	Details