1-Hydroxy-3-(methylpentylamino)-propylidene-1,1-bisphosphonic acid as a potent inhibitor of squalene synthase

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...

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Bibliographic Details
Published inArzneimittel-Forschung Vol. 46; no. 8; p. 759
Main Authors Amin, D, Cornell, S A, Perrone, M H, Bilder, G E
Format Journal Article
LanguageEnglish
Published Germany 01.08.1996
Subjects
Animals
Bone Resorption - prevention & control
Caprylates - metabolism
Cell Line
Cell-Free System
Cholesterol - biosynthesis
Diphosphonates - pharmacology
Farnesyl-Diphosphate Farnesyltransferase - antagonists & inhibitors
Lanosterol - biosynthesis
Mevalonic Acid - metabolism
Mice
Microsomes, Liver - drug effects
Microsomes, Liver - enzymology
Rats
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Summary: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.
ISSN:0004-4172