CP-346086: an MTP inhibitor that lowers plasma cholesterol and triglycerides in experimental animals and in humans.
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.
Chandler
Charles E
CE
Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton Laboratories, Pfizer, Inc., Eastern Point Road, Groton, CT 06340, USA.
Wilder
Donald E
DE
Pettini
Judith L
JL
Savoy
Yvette E
YE
Petras
Stephen F
SF
Chang
George
G
Vincent
John
J
Harwood
H James
HJ
D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood / Q000378:metabolism; D001055:Apolipoproteins B / Q000097:blood / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000097:blood / Q000378:metabolism; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007413:Intestinal Mucosa / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D010743:Phospholipids / Q000097:blood / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*
D016632:Apolipoprotein A-I; D001055:Apolipoproteins B; C493884:CP-346086; D002352:Carrier Proteins; D005227:Fatty Acids; D000960:Hypolipidemic Agents; D007546:Isoquinolines; D010743:Phospholipids; D014230:Triazoles; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; D002784:Cholesterol