ABSTRACT
During our effort to design a receptor binding assay to aid in the elucidation of the molecular mechanism of ezetimibe, we prepared a sulfur-35 containing radioligand which exhibits improved potency over the glucuronide conjugate of ezetimibe in both native enterocyte brush border membranes and membranes from cells expressing recombinant NPC1L1. Herein, we describe the different synthetic strategies which were used to obtain this compound as well as its effectiveness in the aforementioned assay.
Subject(s)
Anticholesteremic Agents/chemistry , Azetidines/chemistry , Membrane Proteins/antagonists & inhibitors , Animals , Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/pharmacology , Azetidines/chemical synthesis , Azetidines/pharmacology , Cell Line , Ezetimibe , Glucuronides/chemistry , Humans , Ligands , Membrane Proteins/metabolism , Membrane Transport Proteins , Mice , Protein Binding , Rats , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Sulfur Radioisotopes/chemistryABSTRACT
The synthesis of a number of indole GnRH antagonists is described. Oxidation of the pyridine ring nitrogen, combined with alkylation at the two position, led to a compound with an excellent in vitro activity profile as well as oral bioavailability in both rats and dogs.
