title: Steroidal glycoside cholesterol absorption inhibitors.
abstract: We have explored the use of steroidal glycosides as cholesterol absorption inhibitors which act through an unknown mechanism. The lead for this program was tigogenin cellobioside (1, tiqueside) which is a weak inhibitor (ED50 = 60 mg/kg) as measured in an acute hamster cholesterol absorption assay. Modification of the steroid portion of the molecule led to the discovery of 11-ketotigogenin cellobioside (5, pamaqueside) which has an ED50 of 2 mg/kg. Replacement of the cellobiose with other sugars failed to provide more potent analogs. However, large improvements in potency were realized through modification of the hydroxyl groups on the cellobiose. This strategy ultimately led to the 4", 6"-bis[(2-fluorophenyl)carbamoyl]-beta-D-cellobiosyl derivative of 11-ketotigogenin (51) with an ED50 of 0.025 mg/kg in the hamster assay, as well as the corresponding hecogenin analog 64 (ED50 = 0.07 mg/kg).
authors.affiliation: Central Research Division, Pfizer Inc. Groton, Connecticut 06340, USA. deninm@pfizer.com
authors.forename: M P
authors.initials: MP
authors.lastname: DeNinno
authors.forename: P A
authors.initials: PA
authors.lastname: McCarthy
authors.forename: K C
authors.initials: KC
authors.lastname: Duplantier
authors.forename: C
authors.initials: C
authors.lastname: Eller
authors.forename: J B
authors.initials: JB
authors.lastname: Etienne
authors.forename: M P
authors.initials: MP
authors.lastname: Zawistoski
authors.forename: F W
authors.initials: FW
authors.lastname: Bangerter
authors.forename: C E
authors.initials: CE
authors.lastname: Chandler
authors.forename: L A
authors.initials: LA
authors.lastname: Morehouse
authors.forename: E D
authors.initials: ED
authors.lastname: Sugarman
authors.forename: R W
authors.initials: RW
authors.lastname: Wilkins
authors.forename: H A
authors.initials: HA
authors.lastname: Woody
authors.forename: L M
authors.initials: LM
authors.lastname: Zaccaro
mesh_terms: D000042:Absorption / Q000187:drug effects; D000818:Animals; D002784:Cholesterol / Q000493:pharmacokinetics*; D006224:Cricetinae; D015195:Drug Design; D000960:Hypolipidemic Agents / Q000737:chemistry* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008956:Models, Chemical; D012503:Saponins / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000960:Hypolipidemic Agents; D012503:Saponins; C080606:tiqueside; D002784:Cholesterol; C099629:pamaqueside