(Aryloxy)methylsilane derivatives as new cholesterol biosynthesis inhibitors: synthesis and hypocholesterolemic activity of a new class of squalene epoxidase inhibitors.
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.
Gotteland
J P
JP
Medicinal Chemistry Division, Centre de Recherche Pierre FABRE, Castres, France.
Brunel
I
I
Gendre
F
F
Désiré
J
J
Delhon
A
A
Junquéro
D
D
Oms
P
P
Halazy
S
S
D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002784:Cholesterol / Q000096:biosynthesis*; D006801:Humans; D008099:Liver / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D010105:Oxygenases / Q000037:antagonists & inhibitors*; D051381:Rats; D012821:Silanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D050603:Squalene Monooxygenase; D013552:Swine
D000924:Anticholesteremic Agents; D012821:Silanes; D002784:Cholesterol; D010105:Oxygenases; D050603:Squalene Monooxygenase