| A Small Molecule Inhibitor of Enterocytic Microsomal Triglyceride Transfer Protein; SLx-4090, Biochemical, Pharmacodynamic, Pharmacokinetic and Safety Profile. | |
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MedLine Citation:
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PMID: 21406547 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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First generation microsomal triglyceride transfer protein (MTP) inhibitors were designed to inhibit hepatic MTP and provide a novel treatment of dyslipidemia. Effective at lowering LDL-cholesterol (LDL-C) these inhibitors also elevated liver enzymes and induced hepatic steatosis in animals and humans. MTP is highly expressed in the enterocytes lining the lumen of the jejunum and is critical in the production of chylomicrons assembled from lipid/cholesterol and their transfer into systemic circulation. SLx-4090 was designed to inhibit (IC50 value ~ 8 nM) only MTP localized to enterocytes. In Caco-2 cells SLx-4090 inhibited apolipoproteinB (ApoB; IC50 value ~ 9.6 nM) but not apolipoproteinA1 (ApoA1) secretion. Administered orally to rats SLx-4090 reduced postprandial (PP) lipids by >50% with an ED50 value ~7 mg/kg. SLx-4090 was not detected in the systemic or portal vein serum of animals (LOQ ~ 5 ng/mL) following single or multiple oral doses in fasted rodents. When co-administered with tyloxapol, SLx-4090 did not inhibit the secretion of hepatic triglycerides (TG), consistent with absence of systemic exposure. Chronic treatment with SLx-4090 in mice maintained on high fat diet decreased LDL-C, TG and resulted in weight loss without elevation of liver enzymes or increase in hepatic fat. The compound did not result in toxicity when administered to rats for 90 days at a dose of 1000 mg/kg/day. These data support the concept that the inhibition of enterocytic MTP could serve as a useful strategy in the treatment of metabolic disorders. |
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Authors:
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Enoch Kim; Stewart Campbell; Olivier Schueller; Eric Wong; Bridget Cole; Jay Kuo; John Ferkany; James Ellis; Paul Sweetnam |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-3-15 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: - ISSN: 1521-0103 ISO Abbreviation: - Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-3-16 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1 Surface Logix, Inc.; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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