title: Bioactive metabolites of EM574 and EM523, erythromycin derivatives having strong gastrointestinal motor stimulating activity.
abstract: Two motilides, EM574 (N-demethyl-N-isopropyl-8,9-anhydroerythromycin A 6,9-hemiacetal) and EM523 (N-demethyl-N-ethyl-8,9-anhydroerythromycin A 6,9-hemiacetal) have strong gastrointestinal motor stimulating (GMS) activity. When administered orally to dogs, these agents showed strong GMS activity, but their plasma levels were very low and the metabolites which have been determined so far using the radio-labeled compounds show only weak GMS activity. The findings suggested that unknown bioactive metabolites might be responsible for the GMS activity. From the liver of dogs given EM574 intravenously, two bioactive metabolites, EM574 P1 and P2, were isolated by solvent extraction and chromatography as detected by contractile activity. They both showed the same UV spectra as EM574 and the molecular ion peaks at m/z 760 (MH+) and 602 (MH(+)-cladinose) in the FAB-MS. From 2D-NMR experiments, the structures of EM574 P1 and P2 were unveiled to be the 15- and 14-hydroxyl derivatives of EM574, respectively. EM523 P1 and P2 were also isolated in the same procedure. In order to prepare these bioactive metabolites, EM574 and EM523 were converted enzymatically with dog liver homogenates in the presence of co-enzymes to give the corresponding P1 and P2. The structures of the metabolites are shown in Fig 1. They exhibited stronger contractile activity in vitro and GMS activity in vivo than the parent compounds.
authors.affiliation: Discovery Research Division, Takeda Chemical Industries, Ltd., Ibaraki, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Funabashi
authors.forename: Y
authors.initials: Y
authors.lastname: Maeshiba
authors.forename: N
authors.initials: N
authors.lastname: Inatomi
authors.forename: S
authors.initials: S
authors.lastname: Tanayama
authors.forename: S
authors.initials: S
authors.lastname: Harada
authors.forename: Z
authors.initials: Z
authors.lastname: Itoh
authors.forename: S
authors.initials: S
authors.lastname: Omura
mesh_terms: D000818:Animals; D004285:Dogs; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D011817:Rabbits
chemical_list: D005765:Gastrointestinal Agents; C090116:Idremcinal; D004917:Erythromycin; C061752:EM 523