Synthesis and biological evaluation of novel propylamine derivatives as orally active squalene synthase inhibitors.
Squalene synthase inhibitors are potentially superior hypolipidemic agents. We synthesized novel propylamine derivatives, as well as evaluated their ability to inhibit squalene synthase and their lipid-lowering effects in rats. 1-Allyl-2-[3-(benzylamino)propoxy]-9H-carbazole (YM-75440) demonstrated potent inhibition of the enzyme derived from HepG2 cells with an IC(50) value of 63 nM. It significantly reduced both plasma total cholesterol and plasma triglyceride levels following oral dosing to rats with a reduced tendency to elevate plasma transaminase levels.
Ishihara
Tsukasa
T
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd, Chemistry Laboratories, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. ishihat@yamanouchi.co.jp
Kakuta
Hirotoshi
H
Moritani
Hiroshi
H
Ugawa
Tohru
T
Yanagisawa
Isao
I
D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D011437:Propylamines / Q000008:administration & dosage / Q000138:chemical synthesis*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D011437:Propylamines; D013186:Farnesyl-Diphosphate Farnesyltransferase