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Journal of Lipid Research, Vol. 44, 1887-1901, October 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology

CP-346086

Charles E. Chandler, Donald E. Wilder, Judith L. Pettini, Yvette E. Savoy, Stephen F. Petras, George Chang, John Vincent and H. James Harwood, Jr.¹

Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton Laboratories, Pfizer, Inc., Eastern Point Road, Groton, CT 06340

¹ To whom correspondence should be addressed. e-mail: h_james_harwood{at}groton.pfizer.com

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.

Abbreviations: CETP, cholesterol ester transfer protein; CHD, coronary heart disease; ER, endoplasmic reticulum; MTP, microsomal triglyceride transfer protein

Supplementary key words microsomal triglyceride transfer protein • lipid transfer inhibition • very low density lipoprotein • low density lipoprotein • apolipoprotein B • apolipoprotein A-I • Hep-G2 cells

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