Microsomal triglyceride transfer protein inhibitors: discovery and synthesis of alkyl phosphonates as potent MTP inhibitors and cholesterol lowering agents.
A series of newly synthesized phosphonate esters were evaluated for their effects on microsomal triglyceride transfer protein activity (MTP). The most potent compounds were evaluated for their ability to inhibit lipoprotein secretion in HepG2 cells and to affect VLDL secretion in rats. These inhibitors were also found to lower serum cholesterol levels in a hamster model upon oral dosing.
Magnin
David R
DR
Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. magnind@bms.com
Biller
Scott A
SA
Wetterau
John
J
Robl
Jeffrey A
JA
Dickson
John K
JK
Taunk
Prakash
P
Harrity
Thomas W
TW
Lawrence
R Michael
RM
Sun
C-Q
CQ
Wang
Tammy
T
Logan
Janette
J
Fryszman
Olga
O
Connolly
Fergal
F
Jolibois
Kern
K
Kunselman
Lori
L
D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D015243:Cholesterol, VLDL / Q000378:metabolism; D006224:Cricetinae; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008968:Molecular Conformation; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000924:Anticholesteremic Agents; D002352:Carrier Proteins; D015243:Cholesterol, VLDL; D063065:Organophosphonates; C106092:microsomal triglyceride transfer protein