title: A small-molecule inhibitor of enterocytic microsomal triglyceride transfer protein, SLx-4090: biochemical, pharmacodynamic, pharmacokinetic, and safety profile.
abstract: First-generation microsomal triglyceride transfer protein (MTP) inhibitors were designed to inhibit hepatic MTP and provide a novel treatment of dyslipidemia. Effective at lowering low-density lipoprotein-cholesterol (LDL-C), these inhibitors also elevate liver enzymes and induce 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. 6-(4'-Trifluoromethyl-6-methoxy-biphenyl-2-ylcarboxamido)-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid phenyl ester (SLx-4090) (IC(50) value ∼8 nM) was designed to inhibit only MTP localized to enterocytes. In Caco-2 cells SLx-4090 inhibited apolipoprotein B (IC(50) value ∼9.6 nM) but not apolipoprotein A1 secretion. Administered orally to rats SLx-4090 reduced postprandial lipids by >50% with an ED(50) value ∼7 mg/kg. SLx-4090 was not detected in the systemic or portal vein serum of the animals (lower limit of quantitation ∼5 ng/ml) after single or multiple oral doses in fasted rodents. When coadministered with tyloxapol, SLx-4090 did not inhibit the secretion of hepatic triglycerides (TG), consistent with the absence of systemic exposure. Chronic treatment with SLx-4090 in mice maintained on a high-fat diet decreased LDL-C and TG and resulted in weight loss without the elevation of liver enzymes or an 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 per day. These data support the concept that the inhibition of enterocytic MTP could serve as a useful strategy in the treatment of metabolic disorders.
authors.affiliation: Surface Logix, Inc., 50 Soldiers Field Place, Brighton, MA 02135, USA.
authors.forename: Enoch
authors.initials: E
authors.lastname: Kim
authors.forename: Stewart
authors.initials: S
authors.lastname: Campbell
authors.forename: Olivier
authors.initials: O
authors.lastname: Schueller
authors.forename: Eric
authors.initials: E
authors.lastname: Wong
authors.forename: Bridget
authors.initials: B
authors.lastname: Cole
authors.forename: Jay
authors.initials: J
authors.lastname: Kuo
authors.forename: James
authors.initials: J
authors.lastname: Ellis
authors.forename: John
authors.initials: J
authors.lastname: Ferkany
authors.forename: Paul
authors.initials: P
authors.lastname: Sweetnam
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis; D001055:Apolipoproteins B / Q000378:metabolism; D001549:Benzamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D008078:Cholesterol, LDL / Q000097:blood; D004353:Drug Evaluation, Preclinical; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D057847:Lipid Regulating Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability / Q000187:drug effects; D019518:Postprandial Period; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood
chemical_list: C559489:6-(4'-trifluoromethyl-6-methoxybiphenyl-2-ylcarboxamido)-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid phenyl ester; D016632:Apolipoprotein A-I; D001055:Apolipoproteins B; D001549:Benzamides; C493884:CP-346086; D002352:Carrier Proteins; D008078:Cholesterol, LDL; D007546:Isoquinolines; D057847:Lipid Regulating Agents; D014230:Triazoles; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein