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(Aryloxy)methylsilane derivatives as new cholesterol biosynthesis inhibitors: synthesis and hypocholesterolemic activity of a new class of squalene epoxidase inhibitors. 1995

J P Gotteland, and I Brunel, and F Gendre, and J Désiré, and A Delhon, and D Junquéro, and P Oms, and S Halazy
Medicinal Chemistry Division, Centre de Recherche Pierre FABRE, Castres, France.

A series of 3-substituted (aryloxy)silane derivatives of benzylamine (4, 4', or 4") was synthesized and evaluated for hypocholesterolemic activity. Most of the new silane derivatives were identified as potent inhibitors of pig liver squalene epoxidase with IC50 values in the submicromolar range. In vitro inhibition of cholesterol biosynthesis in Hep-G2 cells was observed with a very good potency for the ene-yne derivatives 4a, 4i, 4n, 4q, and 4u as well as for the yne-yne compound 4". In vivo, 4i, 4u, 4', and 4" were found to decrease cholesterol biosynthesis in rats upon oral administration with ED50 values in the range of 2-7 mg/kg. Therefore, these new (aryloxy)methylsilane derivatives of benzylamine represent a new class of potent squalene epoxidase inhibitors with promising hypocholesterolemic properties.

UI MeSH Term Description Entries
D008099 Liver A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances. Livers
D009682 Magnetic Resonance Spectroscopy Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (MAGNETIC RESONANCE IMAGING). In Vivo NMR Spectroscopy,MR Spectroscopy,Magnetic Resonance,NMR Spectroscopy,NMR Spectroscopy, In Vivo,Nuclear Magnetic Resonance,Spectroscopy, Magnetic Resonance,Spectroscopy, NMR,Spectroscopy, Nuclear Magnetic Resonance,Magnetic Resonance Spectroscopies,Magnetic Resonance, Nuclear,NMR Spectroscopies,Resonance Spectroscopy, Magnetic,Resonance, Magnetic,Resonance, Nuclear Magnetic,Spectroscopies, NMR,Spectroscopy, MR
D010105 Oxygenases Oxidases that specifically introduce DIOXYGEN-derived oxygen atoms into a variety of organic molecules. Oxygenase
D002784 Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Epicholesterol
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000924 Anticholesteremic Agents Substances used to lower plasma CHOLESTEROL levels. Cholesterol Inhibitors,Hypocholesteremic Agents,Anticholesteremic Drugs,Anticholesteremics,Inhibitors, Cholesterol,Agents, Anticholesteremic,Agents, Hypocholesteremic,Drugs, Anticholesteremic
D012821 Silanes Compounds similar to hydrocarbons in which a tetravalent silicon atom replaces the carbon atom. They are very reactive, ignite in air, and form useful derivatives. Silane
D013552 Swine Any of various animals that constitute the family Suidae and comprise stout-bodied, short-legged omnivorous mammals with thick skin, usually covered with coarse bristles, a rather long mobile snout, and small tail. Included are the genera Babyrousa, Phacochoerus (wart hogs), and Sus, the latter containing the domestic pig (see SUS SCROFA). Phacochoerus,Pigs,Suidae,Warthogs,Wart Hogs,Hog, Wart,Hogs, Wart,Wart Hog
D050603 Squalene Monooxygenase The second enzyme in the committed pathway for CHOLESTEROL biosynthesis, this enzyme catalyzes the first oxygenation step in the biosynthesis of STEROLS and is thought to be a rate limiting enzyme in this pathway. Specifically, this enzyme catalyzes the conversion of SQUALENE to (S)-squalene-2,3-epoxide. Squalene Epoxidase,Squalene Monooxygenase (2,3-Epoxidizing),Epoxidase, Squalene,Monooxygenase, Squalene

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