title: Castanospermine-glucosides are potent, selective, long-acting sucrase inhibitors.
abstract: Castanospermine-glucosides (CS-glcs) are new compounds which have been evaluated as glycohydrolase inhibitors in rats. 7-O-alpha-D-Glucopyranosyl-CS (7 alpha-glc-CS) and 8 alpha-glc-CS were potent sucrase inhibitors with IC50s of 40 and 30 nM, respectively. Their sucrase inhibition was poorly reversible. They were much weaker liver lysosomal alpha-glucosidase inhibitors with IC50s of 40,000 nM. 1 alpha-glc-CS and 8 beta-glc-CS were both weaker and less selective sucrase inhibitors. In vivo, 7 alpha-glc-CS and 8 alpha-glc-CS effectively reduced the glycemic response to an oral 2 g/kg sucrose load at doses less than or equal to 1 mg/kg. 8 alpha-glc-CS was effective when administered up to 4 hr before sucrose. The known glucohydrolase inhibitors 1-deoxynojirimycin and N-hydroxyethyl-1-deoxy-nojirimycin were also potent sucrase inhibitors (IC50s = 200 and 400 nM, respectively) but their sucrase inhibition was readily reversible in vitro and their in vivo duration of action was much shorter than for the CS-glcs. Among the glucohydrolase inhibitors tested, the prolonged in vivo duration of action could be predicted by poor reversibility from sucrase. These CS-glcs provide a new generation of sucrase inhibitors which may be useful in the treatment of diabetes mellitus.
authors.affiliation: Merrell Dow Research Institute, Cincinnati, Ohio.
authors.forename: K M
authors.initials: KM
authors.lastname: Robinson
authors.forename: B L
authors.initials: BL
authors.lastname: Rhinehart
authors.forename: M E
authors.initials: ME
authors.lastname: Begovic
authors.forename: C H
authors.initials: CH
authors.lastname: King
authors.forename: P S
authors.initials: PS
authors.lastname: Liu
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D005960:Glucosides / Q000494:pharmacology*; D065089:Glycoside Hydrolase Inhibitors; D006027:Glycosides / Q000494:pharmacology*; D066298:In Vitro Techniques; D007212:Indolizines; D007422:Intestines / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008247:Lysosomes / Q000201:enzymology; D051381:Rats; D013393:Sucrase / Q000037:antagonists & inhibitors*; D054836:Indolizidines
chemical_list: D000470:Alkaloids; D001786:Blood Glucose; D005960:Glucosides; D065089:Glycoside Hydrolase Inhibitors; D006027:Glycosides; D007212:Indolizines; D013393:Sucrase; C037806:castanospermine; D054836:Indolizidines