Target Validation Information
Target ID T81850
Target Name Squalene synthetase
Target Type
Discontinued
Drug Potency against Target Zaragozic Acid C Drug Info IC50 = 0.4 nM
Zaragozic Acid D2 Drug Info IC50 = 2 nM
2-[4-(2-Thienyl)phenyl]-4-methylmorpholin-2-ol Drug Info IC50 = 5000 nM [529661]
BMS-187745 Drug Info IC50 = 23 nM [529947]
A-87049 Drug Info IC50 = 37 nM [534419]
ZARAGOZIC ACID B Drug Info IC50 = 0.2 nM
3-[7'-(Methoxy)-napht-2'-yl]-quinuclidine-2-ene Drug Info IC50 = 2800 nM [528993]
3-[1'-{4'-(Benzyloxy)-phenyl}]-quinuclidine-2-ene Drug Info IC50 = 250 nM [528993]
Lapaquistat acetate Drug Info IC50 = 78 nM [552733]
ZARAGOZIC ACIDS A Drug Info IC50 = 0.5 nM
Zaragozic Acid D Drug Info IC50 = 6 nM
SQ-34919 Drug Info IC50 = 17 nM
ER-119884 Drug Info IC50 = 6 nM [528739]
Action against Disease Model Lapaquistat acetate In HepG2 cells, TAK-475 and its pharmacologically active metabolite, T-91485, increased the binding of (125)I-low-density lipoprotein (LDL) to LDL receptors. TAK-475 inhibited hepatic cholesterol biosynthesis in rats (ED(50), 2.9 mg kg(-1)) and showed lipid-lowering effects in beagle dogs, marmosets, cynomolgus monkeys and Wistar fatty rats. In marmosets, TAK-475 (30, 100 mgkg(-1), p.o., for 4 days) lowered both plasma non-high-density lipoprotein (HDL) cholesterol and triglyceride, but did not affect plasma HDL cholesterol. On the other hand, atorvastatin (10, 30 mg kg(-1), p.o., for 4 days) lowered the levels of all these lipids. A correlation between decrease in triglyceride and increase in HDL cholesterol was observed, and TAK-475 increased HDL cholesterol with a smaller decrease in triglyceride than did atorvastatin. TAK-475 (60 mg kg(-1), p.o., for 15 days) suppressed the rate of triglyceride secretion from the liver in hypertriglyceridemic Wistar fatty rats, which show an enhanced triglyceride secretion rate from the liver compared with their lean littermates. [552354] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations Using conditional gene inactivation in the mouse, we disrupted the squalene synthase gene (fdft1), which is critical for cholesterol synthesis, in cerebellar granule cells and some precerebellar nuclei. Mutant mice showed no histological signs of neuronal degeneration, displayed ultrastructurally normal synapses, and exhibited normal motor coordination. This revealed that these adult neurons do not require cell-autonomous cholesterol synthesis for survival or function.
References
Ref 529661J Med Chem. 2008 Sep 25;51(18):5861-5.Lipid-lowering (hetero)aromatic tetrahydro-1,4-oxazine derivatives with antioxidant and squalene synthase inhibitory activity.
Ref 529947J Med Chem. 2009 Feb 26;52(4):976-88.Phosphonosulfonates are potent, selective inhibitors of dehydrosqualene synthase and staphyloxanthin biosynthesis in Staphylococcus aureus.
Ref 534419J Med Chem. 1997 Jul 4;40(14):2123-5.(1 alpha, 2 beta, 3 beta, 4 alpha)-1,2-bis[N-propyl-N-(4-phenoxybenzyl) amino]carbonyl]cyclobutane-3,4-dicarboxylic acid (A-87049): a novel potent squalene synthase inhibitor.
Ref 528993Antimicrob Agents Chemother. 2007 Nov;51(11):4049-61. Epub 2007 Aug 20.Quinuclidine derivatives as potential antiparasitics.
Ref 528993Antimicrob Agents Chemother. 2007 Nov;51(11):4049-61. Epub 2007 Aug 20.Quinuclidine derivatives as potential antiparasitics.
Ref 552733EP2306 [2-(4-biphenyl)-4-methyl-octahydro-1,4-benzoxazin-2-ol, hydrobromide], a novel squalene synthase inhibitor, reduces atherosclerosis in the cholesterol-fed rabbit. J Pharmacol Exp Ther. 2007 Dec;323(3):794-804. Epub 2007 Sep 5.
Ref 552354Lipid-lowering properties of TAK-475, a squalene synthase inhibitor, in vivo and in vitro. Br J Pharmacol. 2003 Jul;139(5):911-8.
Ref 528739Antimicrob Agents Chemother. 2007 Jun;51(6):2123-9. Epub 2007 Mar 19.Kinetic characterization of squalene synthase from Trypanosoma cruzi: selective inhibition by quinuclidine derivatives.

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