title: Microsomal triglyceride transfer protein inhibitors: discovery and synthesis of alkyl phosphonates as potent MTP inhibitors and cholesterol lowering agents.
abstract: 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.
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. magnind@bms.com
authors.forename: David R
authors.initials: DR
authors.lastname: Magnin
authors.forename: Scott A
authors.initials: SA
authors.lastname: Biller
authors.forename: John
authors.initials: J
authors.lastname: Wetterau
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Robl
authors.forename: John K
authors.initials: JK
authors.lastname: Dickson
authors.forename: Prakash
authors.initials: P
authors.lastname: Taunk
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Harrity
authors.forename: R Michael
authors.initials: RM
authors.lastname: Lawrence
authors.forename: C-Q
authors.initials: CQ
authors.lastname: Sun
authors.forename: Tammy
authors.initials: T
authors.lastname: Wang
authors.forename: Janette
authors.initials: J
authors.lastname: Logan
authors.forename: Olga
authors.initials: O
authors.lastname: Fryszman
authors.forename: Fergal
authors.initials: F
authors.lastname: Connolly
authors.forename: Kern
authors.initials: K
authors.lastname: Jolibois
authors.forename: Lori
authors.initials: L
authors.lastname: Kunselman
mesh_terms: 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
chemical_list: D000924:Anticholesteremic Agents; D002352:Carrier Proteins; D015243:Cholesterol, VLDL; D063065:Organophosphonates; C106092:microsomal triglyceride transfer protein