2-Azetidinone Cholesterol Absorption Inhibitors:  Structure−Activity Relationships on the Heterocyclic Nucleus

Clader, John W.; Burnett, Duane A.; Caplen, Mary Ann; Domalski, Martin S.; Dugar, Sundeep; Vaccaro, Wayne; Sher, Rosy; Browne, Margaret; Zhao, Hongrong; Burrier, Robert E.; Salisbury, Brian; Davis, Harry R.

doi:10.1021/jm960405n

Cited by 128 publications

(91 citation statements)

References 18 publications

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“…In contrast, the addition of a protective second glucuronide group to the first glucuronide moiety (SCH61159) causes the K i value to revert to that observed for the nonglucuronidated form. It has been reported previously that hydroxylation of the 3-phenylpropyl side chain improves in vivo potency of this class of compounds (Clader et al, 1996;Burnett, 2004). Consistent with that conclusion, compounds that lack the hydroxyl group at the 3-phenylpropyl side chain exhibit decreased (SCH58832) or total loss (SCH60179 and SCH50032) of NPC1L1 binding activity.…”

Section: Speciessupporting

confidence: 83%

In Vivo Responsiveness to Ezetimibe Correlates with Niemann-Pick C1 Like-1 (NPC1L1) Binding Affinity: Comparison of Multiple Species NPC1L1 Orthologs

Hawes¹,

O’Neill²,

Yao³

et al. 2007

Molecular Pharmacology

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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. After oral administration, ezetimibe is glucuronidated. Both ezetimibe and the glucuronide lower plasma cholesterol; however, the glucuronide exhibits greater potency. Recent identification of Niemann-Pick C1 Like-1 (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 Ͼ dog Ͼ hamster and rat Ͼ Ͼ 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 as 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.Hypercholesterolemia is linked to cardiovascular disease, myocardial infarction, and stroke. Blood cholesterol levels are regulated by several components, including de novo synthesis, dietary cholesterol absorption, and biliary clearance and excretion. Alteration of the rate of any of these processes can drastically affect whole-body cholesterol levels. Several pharmaceutical therapeutics have been developed that inhibit cholesterol synthesis. These agents, collectively referred to as statins, inhibit the enzyme 3-hydroxymethylglutaryl coenzyme A reductase to effectively reduce blood cholesterol levels and represent the standard of care for treatment of dyslipidemia. A new class of cholesterol-lowering therapeutics, called 2-azetidinones, decreases plasma cholesterol levels by blocking intestinal absorption of cholesterol. Ezetimibe (Zetia; Merck/Schering-Plough, Kenilworth, NJ), the first-in-class representative of the 2-azetidinones, blocks both dietary and biliary cholesterol absorption in the Article, publication date, and citation information can be found at

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Section: Speciessupporting

confidence: 83%

In Vivo Responsiveness to Ezetimibe Correlates with Niemann-Pick C1 Like-1 (NPC1L1) Binding Affinity: Comparison of Multiple Species NPC1L1 Orthologs

Hawes¹,

O’Neill²,

Yao³

et al. 2007

Molecular Pharmacology

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“…7 chloride was explored [24]. This method uses half an equivalent of TiCl 4 in the condensation of the appropriate aniline and benzophenone using tri-n-butylamine as the base.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Synthesis, biochemical and molecular modelling studies of antiproliferative azetidinones causing microtubule disruption and mitotic catastrophe

O’Boyle

Carr

Greene

et al. 2011

European Journal of Medicinal Chemistry

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“…Based on the structure-activity relationships for 2-azetidinone cholesterol absorption inhibitors (12,16,30) we have synthesized an Ezetimibe affinity matrix (Fig. 1G).…”

Section: The Luminal Side Of the Enterocyte Brush Border Membranementioning

confidence: 99%

Aminopeptidase N (CD13) Is a Molecular Target of the Cholesterol Absorption Inhibitor Ezetimibe in the Enterocyte Brush Border Membrane

Kramer¹,

Girbig²,

Corsiero³

et al. 2005

Journal of Biological Chemistry

118

108

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Intestinal cholesterol absorption is an important regulator of serum cholesterol levels. Ezetimibe is a specific inhibitor of intestinal cholesterol absorption recently introduced into medical practice; its mechanism of action, however, is still unknown. Ezetimibe neither influences the release of cholesterol from mixed micelles in the gut lumen nor the transfer of cholesterol to the enterocyte brush border membrane.

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2-Azetidinone Cholesterol Absorption Inhibitors: Structure−Activity Relationships on the Heterocyclic Nucleus

Cited by 128 publications

References 18 publications

In Vivo Responsiveness to Ezetimibe Correlates with Niemann-Pick C1 Like-1 (NPC1L1) Binding Affinity: Comparison of Multiple Species NPC1L1 Orthologs

In Vivo Responsiveness to Ezetimibe Correlates with Niemann-Pick C1 Like-1 (NPC1L1) Binding Affinity: Comparison of Multiple Species NPC1L1 Orthologs

Synthesis, biochemical and molecular modelling studies of antiproliferative azetidinones causing microtubule disruption and mitotic catastrophe

Aminopeptidase N (CD13) Is a Molecular Target of the Cholesterol Absorption Inhibitor Ezetimibe in the Enterocyte Brush Border Membrane

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