title: Lipophilic 1,1-bisphosphonates are potent squalene synthase inhibitors and orally active cholesterol lowering agents in vivo.
abstract: Squalene synthase catalyzes the reductive dimerization of two molecules of farnesyl diphosphate to form squalene at the final branchpoint of the cholesterol biosynthetic pathway. We report herein that isoprenyl 1,1-bisphosphonates and related analogs are potent inhibitors of rat microsomal squalene synthase (I50 = 0.7-32 nM). In addition, members of this family are potent inhibitors of cholesterol biosynthesis in rats on intravenous and oral dosing, as well as cholesterol lowering agents in rats and hamsters. Significant inhibition of cholesterol biosynthesis in rats by lovastatin occurs with a concomitant inhibition of dolichol and coenzyme-Q9 synthesis. In contrast, bisphosphonate 4 has no effect on dolichol and coenzyme-Q9 biosynthesis in rats under conditions where cholesterol biosynthesis is > 90% inhibited.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Department of Metabolic Diseases, Princeton, New Jersey 08543-4000.
authors.forename: C P
authors.initials: CP
authors.lastname: Ciosek
authors.forename: D R
authors.initials: DR
authors.lastname: Magnin
authors.forename: T W
authors.initials: TW
authors.lastname: Harrity
authors.forename: J V
authors.initials: JV
authors.lastname: Logan
authors.forename: J K
authors.initials: JK
authors.lastname: Dickson
authors.forename: E M
authors.initials: EM
authors.lastname: Gordon
authors.forename: K A
authors.initials: KA
authors.lastname: Hamilton
authors.forename: K G
authors.initials: KG
authors.lastname: Jolibois
authors.forename: L K
authors.initials: LK
authors.lastname: Kunselman
authors.forename: R M
authors.initials: RM
authors.lastname: Lawrence
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood*; D003067:Coenzymes; D006224:Cricetinae; D004164:Diphosphonates / Q000008:administration & dosage / Q000494:pharmacology*; D004286:Dolichols / Q000378:metabolism; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology; D008297:Male; D008647:Mesocricetus; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013185:Squalene / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000096:biosynthesis
chemical_list: D000924:Anticholesteremic Agents; D003067:Coenzymes; D004164:Diphosphonates; D004286:Dolichols; D014451:Ubiquinone; D013185:Squalene; D002784:Cholesterol; D008148:Lovastatin; D013186:Farnesyl-Diphosphate Farnesyltransferase; C024989:coenzyme Q10