ABSTRACT
SAR studies directed towards the optimization of 2-azetidinone cholesterol absorption inhibitors led to the discovery of 11a, the most potent cholesterol absorption inhibitor yet identified.
Subject(s)
Anticholesteremic Agents/chemistry , Anticholesteremic Agents/pharmacology , Azetidines/pharmacology , Cholesterol/metabolism , Animals , Azetidines/chemistry , Cholesterol/blood , Cricetinae , Liver/drug effects , Liver/metabolism , Magnetic Resonance Spectroscopy , Mass Spectrometry , Structure-Activity RelationshipABSTRACT
The asymmetric synthesis of a glucuronide conjugate of the 2-azetidinone cholesterol absorption inhibitor Sch 48461 was accomplished to confirm the structure of a metabolite isolated from in vivo sources. Key features of this article include the asymmetric synthesis of 2-azetidinones by Evan's chiral oxazolidinone methodology and glucuronide formation by a Mitsunobu protocol.
Subject(s)
Anticholesteremic Agents/pharmacology , Azetidines/pharmacology , Carbohydrates/chemistry , Animals , Anticholesteremic Agents/chemistry , Azetidines/chemistry , Cricetinae , Molecular StructureABSTRACT
A glucuronide conjugate of the potent 2-azetidinone cholesterol absorption inhibitor Sch 58235 was synthesized to confirm the structure of a metabolite isolated from in vivo sources. A series of 2-azetidinone glycosides was prepared via Schmidt trichloroimidate methodology. Enhanced cholesterol absorption inhibition was achieved by modification of the sugar moiety.
Subject(s)
Anticholesteremic Agents/chemistry , Anticholesteremic Agents/pharmacology , Azetidines/chemistry , Azetidines/pharmacology , Carbohydrates/chemistry , Animals , Cholesterol/blood , Cholesterol/metabolism , Chromatography, High Pressure Liquid , Cricetinae , Liver/drug effects , Liver/metabolism , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Structure , Structure-Activity RelationshipABSTRACT
Metabolism initiated SAR studies led to the discovery of a new class of potent 2-azetidinone cholesterol absorption inhibitors. These studies found that a heteroatom at the para position of the C-4 phenyl ring is not a requirement for cholesterol absorption inhibition as was suggested by earlier findings. Substitution of Ph-linker-COOR for PhOMe at the C-4 position enhanced cholesterol absorption inhibition.