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

SJ Shaw, Y Chen, H Zheng, H Fu… - Journal of medicinal …, 2009 - ACS Publications
SJ Shaw, Y Chen, H Zheng, H Fu, MA Burlingame, S Marquez, Y Li, M Claypool…
Journal of medicinal chemistry, 2009ACS Publications
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 …
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.
ACS Publications