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Received for publication June 13, 2006.
Revised September 27, 2006.
Accepted for publication September 27, 2006.
Ezetimibe is the first in class 2-azetidinone that decreases plasma cholesterol by blocking intestinal cholesterol absorption. Ezetimibe effectively reduces plasma cholesterol in several species including human, monkey, dog, hamster, rat, and mouse, but the potency ranges widely. One potential factor responsible for this variation in responsiveness is diversity in ezetimibe metabolism. Following oral administration, ezetimibe is glucuronidated. Both ezetimibe and the glucuronide lower plasma cholesterol, however the glucuronide exhibits greater potency. Recent identification of NPC1L1 as the molecular target of ezetimibe enables direct binding studies to be performed. Here, we report the cloning of NPC1L1 derived from multiple species and assess amino acid sequence homology among human, monkey, dog, hamster, rat, and mouse. The rank order of affinity of glucuronidated ezetimibe for NPC1L1 in each species correlates with the rank order of in vivo activity with monkey > dog > hamster and rat >> mouse. Ezetimibe analogs that bind to NPC1L1 exhibit in vivo cholesterol lowering activity whereas compounds that do not bind NPC1L1 are inactive. Specific structural components of ezetimibe are identified critical for binding to NPC1L1. The results demonstrate that small variations in ezetimibe structure or in NPC1L1 amino acid sequence can profoundly influence ezetimibe/NPC1L1 interaction and consequently in vivo activity. The results demonstrate that the ability of compounds to bind to NPC1L1 is the major determinant of in vivo responsiveness.
Key words:
Structure determinations, Structure-activity relationships and modeling, Func. analysis receptor/ion channel mutants, Protein-binding, Structure/function/mechanism, Cholesterol metabolism/lipoproteins
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