Motilides, macrolides with gastrointestinal motor stimulating activity. I. O-substituted and tertiary N-substituted derivatives of 8,9-anhydroerythromycin A 6,9-hemiacetal.
Chemical modifications of 8,9-anhydroerythromycin A 6,9-hemiacetal (1), which showed gastrointestinal motor stimulating (GMS) activity 10 times more potent than that of erythromycin A (EM-A), were undertaken to search for derivatives having stronger GMS activity and no antimicrobial activity; details are described in this and a subsequent paper. Displacement of a methyl group of the dimethylamino group of 1 with an ethyl group and an isopropyl group provided de(N-methyl-N-ethyl-8,9-anhydroerythromycin A 6,9-hemiacetal (55) and de(N-methyl)-N-isopropyl-8,9-anhydroerythromycin A 6,9-hemiacetal (58), respectively. They showed significant GMS activity and no antibacterial activity. In particular, the GMS activity of 58 was increased to 248 times that of EM-A. EM-A and the derivatives obtained in this study mimic exogenous motilin in the dog. The name "motilide", meaning a motilin-like macrolide, is proposed for this new family of macrolide compounds.
Tsuzuki
K
K
Sunazuka
T
T
Marui
S
S
Toyoda
H
H
Omura
S
S
Inatomi
N
N
Itoh
Z
Z
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis; D001419:Bacteria / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D013268:Stimulation, Chemical
D000900:Anti-Bacterial Agents; D004917:Erythromycin