title: 1-Hydroxy-3-(methylpentylamino)-propylidene-1,1-bisphosphonic acid as a potent inhibitor of squalene synthase.
abstract: Squalene synthase, the first committed enzyme for sterol synthesis, converts farnesyl pyrophosphate to squalene with presqualene pyrophosphate as an intermediate. It was discovered that BM 21.0955 (1-hydroxy-3-(methylpentylamino)-propylidene-1,1-bisphosphon ic acid), in development for the treatment of bone disorders, inhibited rat liver microsomal squalene synthase (K(i) = nmol/l). BM 21.0955 also inhibited sterol biosynthesis from mevalonate (IC50 = 42 nmol/l), and cholesterol biosynthesis in J774 cells (IC50 = mumol/l). Structural modifications on this molecule to make it more lipophilic may result in a new class of cholesterol-lowering agents.
authors.affiliation: Rhône-Poulenc Rorer Central Research, Collegeville, PA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Amin
authors.forename: S A
authors.initials: SA
authors.lastname: Cornell
authors.forename: M H
authors.initials: MH
authors.lastname: Perrone
authors.forename: G E
authors.initials: GE
authors.lastname: Bilder
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000517:prevention & control; D002210:Caprylates / Q000378:metabolism; D002460:Cell Line; D002474:Cell-Free System; D002784:Cholesterol / Q000096:biosynthesis*; D004164:Diphosphonates / Q000494:pharmacology*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D000077557:Ibandronic Acid; D007810:Lanosterol / Q000096:biosynthesis; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D051381:Rats
chemical_list: D002210:Caprylates; D004164:Diphosphonates; D007810:Lanosterol; D002784:Cholesterol; D013186:Farnesyl-Diphosphate Farnesyltransferase; C031492:octanoic acid; D008798:Mevalonic Acid; D000077557:Ibandronic Acid