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Papers In Press, published online ahead of print July 1, 2003
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Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, CT 06340
Corresponding Author: h_james_harwood{at}groton.pfizer.com
MTP plays an obligatory role in the assembly and secretion of triglyceride-rich, apoB-containing lipoproteins. MTP inhibition, thus has the potential to interfere with secretion of triglyceride-rich lipoproteins from the liver and intestine and thereby favorably affect hyperlipidemia. An inhibitor of MTP, CP-346086 (4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(2H-[1,2,4]triazol-3-ylmethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide), was identified that dose dependently inhibited human and rodent MTP activity (IC50 = 2.0 nM). In Hep-G2 cells CP-346086 inhibited apoB and triglyceride secretion (IC50 = 2.6 nM) without affecting either apoA1 secretion, or cholesterol, fatty acid, or triglyceride synthesis. When administered orally to rats or mice, CP-346086 lowered plasma triglycerides in a dose-dependent manner (ED30 = 1.3 mg/kg) 2 hr after a single dose. Co-administration with Tyloxapol demonstrated that triglyceride lowering was due to inhibition of hepatic and intestinal triglyceride secretion. A 2-week treatment with CP-346086 lowered plasma total, VLDL, and LDL cholesterol and triglycerides in a dose-dependent manner with 23%, 33%, 75%, and 62% respective reductions occurring at 10 mg/kg/day. In these animals, MTP inhibition by CP-346086 resulted in increases in both liver and intestinal triglyceride content when CP-346086 was administered in close temporal proximity to feeding. However, when dosed away from meals, only hepatic triglyceride levels were increased. When administered as a single oral dose to healthy human volunteers, CP-346086 reduced plasma triglycerides and VLDL cholesterol in a dose-dependent manner with ED50 values of 10 mg and 3 mg and maximal inhibition (100 mg) of 66% and 87% when measured 4 hrs after treatment. After 2-week treatment at a dose of 30 mg/day, CP-346086 reduced plasma total and LDL cholesterol, and triglycerides by 47%, 72% and 75%, relative to either individual baseline values or placebo, with little change in HDL cholesterol. Together, these data support further evaluation of CP-346086 in hyperlipidemia.
Revised on June 3, 2003
Accepted on June 23, 2003
CP-346086: a microsomal triglyceride transfer protein inhibitor that lowers plasma total, VLDL, and LDL cholesterol and triglycerides by up to 70% in experimental animals and in humans
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