PT - JOURNAL ARTICLE AU - Yasuko Mera AU - Naoya Odani AU - Takashi Kawai AU - Takahiro Hata AU - Masahiro Suzuki AU - Atsushi Hagiwara AU - Takeo Katsushima AU - Makoto Kakutani TI - Pharmacological Characterization of Diethyl-2-({3-dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}acetyloxymethyl)-2-phenylmalonate (JTT-130), an Intestine-Specific Inhibitor of Microsomal Triglyceride Transfer Protein AID - 10.1124/jpet.110.173807 DP - 2011 Feb 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 321--327 VI - 336 IP - 2 4099 - http://jpet.aspetjournals.org/content/336/2/321.short 4100 - http://jpet.aspetjournals.org/content/336/2/321.full SO - J Pharmacol Exp Ther2011 Feb 01; 336 AB - Inhibitors of microsomal triglyceride transfer protein (MTP) expressed in the liver and small intestine are potential candidates for lipid-lowering agents. However, inhibition of hepatic MTP could lead to significant safety issues such as fatty liver disease. To develop a specific inhibitor of intestinal MTP, JTT-130 [diethyl-2-({3-dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}acetyloxymethyl)-2-phenylmalonate], was designed to be rapidly hydrolyzed in the absorption process. Here, we describe JTT-130, an intestine-specific MTP inhibitor, and evaluate its pharmacological properties. In in vitro metabolic stability tests, JTT-130 was readily hydrolyzed during incubation with liver S9 from humans, hamsters, and rats. In an in vitro triglyceride (TG) transfer assay with human intestinal MTP, JTT-130 potently inhibited TG transfer activity with an IC50 value of 0.83 nM. When orally administered to hamsters, JTT-130 significantly suppressed an increase in chylomicron-TG after olive oil loading at 0.3 mg/kg and above but did not inhibit TG secretion from the liver at doses of up to 1000 mg/kg, indicating an inhibitory action highly specific for the small intestine. In rats orally administered [14C]triolein, JTT-130 potently suppressed an increase in blood 14C radioactivity and increased 14C radioactivity in the upper small intestine and the intestinal lumen. In hyperlipidemic hamsters fed a high-fat and high-cholesterol diet, repeated dosing with JTT-130 for 2 weeks reduced TG and cholesterol levels in the plasma and TG content in the liver. These results indicated that JTT-130 is a potent inhibitor specific to intestinal MTP and suggested that JTT-130 would be a useful compound for the treatment of dyslipidemia without inducing hepatotoxicity.