CP-346086: an MTP inhibitor that lowers plasma cholesterol and triglycerides in experimental animals and in humans

• Published in: Journal of lipid research 2003-10, Vol.44 (10), p.1887
• Main Authors: Chandler, Charles E, Wilder, Donald E, Pettini, Judith L, Savoy, Yvette E, Petras, Stephen F, Chang, George, Vincent, John, Harwood, Jr, H James
• Format: Article
• Language: English
• Subjects: Animals; Apolipoprotein A-I - blood; Apolipoprotein A-I - metabolism; Apolipoproteins B - blood; Apolipoproteins B - metabolism; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - metabolism; Cell Line; Cholesterol - blood; Cholesterol - metabolism; Dose-Response Relationship, Drug; Fatty Acids - blood; Fatty Acids - metabolism; Humans; Hypolipidemic Agents - pharmacology; Inhibitory Concentration 50; Intestinal Mucosa - metabolism; Isoquinolines - pharmacology; Liver - metabolism; Mice; Phospholipids - blood; Phospholipids - metabolism; Rats; Rats, Sprague-Dawley; Time Factors; Triazoles - pharmacology; Triglycerides - blood; Triglycerides - metabolism
• ISSN: 0022-2275
• DOI: 10.1194/jlr.M300094-JLR200

A microsomal triglyceride transfer protein (MTP) inhibitor, CP-346086, was identified that inhibited both human and rodent MTP activity [concentration giving half-maximal inhibition (IC50) 2.0 nM]. In Hep-G2 cells, CP-346086 inhibited apolipoprotein B (apoB) and triglyceride secretion (IC50 2.6 nM) without affecting apoA-I secretion or lipid synthesis. When administered orally to rats or mice, CP-346086 lowered plasma triglycerides [dose giving 30% triglyceride lowering (ED30) 1.3 mg/kg] 2 h after a single dose. Coadministration with Tyloxapol demonstrated that triglyceride lowering was due to inhibition of hepatic and intestinal triglyceride secretion. A 2 week treatment with CP-346086 lowered total, VLDL, and LDL cholesterol and triglycerides dose dependently with 23%, 33%, 75%, and 62% reductions at 10 mg/kg/day. In these animals, MTP inhibition resulted in increased liver and intestinal triglycerides when CP-346086 was administered with food. When dosed away from meals, however, only hepatic triglycerides were increased. When administered as a single oral dose to healthy human volunteers, CP-346086 reduced plasma triglycerides and VLDL cholesterol dose dependently with ED50s of 10 mg and 3 mg, and maximal inhibition (100 mg) of 66% and 87% when measured 4 h after treatment. After a 2 week treatment (30 mg/day), CP-346086 reduced total and LDL cholesterol and triglycerides by 47%, 72%, and 75%, relative to either individual baselines or placebo, with little change in HDL cholesterol. Together, these data support further evaluation of CP-346086 in hyperlipidemia.