Target Validation Information
TTD ID	T81850
Target Name	Squalene synthetase (FDFT1)
Type of Target	Discontinued
Drug Potency against Target	Lapaquistat acetate	Drug Info	IC50 = 78 nM	[7]
	2-[4-(2-Thienyl)phenyl]-4-methylmorpholin-2-ol	Drug Info	IC50 = 5000 nM	[3]
	3-[1'-{4'-(Benzyloxy)-phenyl}]-quinuclidine-2-ene	Drug Info	IC50 = 250 nM	[2]
	3-[7'-(Methoxy)-napht-2'-yl]-quinuclidine-2-ene	Drug Info	IC50 = 2800 nM	[2]
	A-87049	Drug Info	IC50 = 37 nM	[5]
	BMS-187745	Drug Info	IC50 = 23 nM	[4]
	ER-119884	Drug Info	IC50 = 6 nM	[1]
	SQ-34919	Drug Info	IC50 = 17 nM
	Squalestatin 1	Drug Info	IC50 = 0.5 nM
	ZARAGOZIC ACID B	Drug Info	IC50 = 0.2 nM
	Zaragozic Acid C	Drug Info	IC50 = 0.4 nM
	Zaragozic Acid D	Drug Info	IC50 = 6 nM
	Zaragozic Acid D2	Drug Info	IC50 = 2 nM
Action against Disease Model	Lapaquistat acetate	Drug Info	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.	[6]
References
REF 1	Kinetic characterization of squalene synthase from Trypanosoma cruzi: selective inhibition by quinuclidine derivatives. Antimicrob Agents Chemother. 2007 Jun;51(6):2123-9.
REF 2	Quinuclidine derivatives as potential antiparasitics. Antimicrob Agents Chemother. 2007 Nov;51(11):4049-61.
REF 3	Lipid-lowering (hetero)aromatic tetrahydro-1,4-oxazine derivatives with antioxidant and squalene synthase inhibitory activity. J Med Chem. 2008 Sep 25;51(18):5861-5.
REF 4	Phosphonosulfonates are potent, selective inhibitors of dehydrosqualene synthase and staphyloxanthin biosynthesis in Staphylococcus aureus. J Med Chem. 2009 Feb 26;52(4):976-88.
REF 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 ... J Med Chem. 1997 Jul 4;40(14):2123-5.
REF 6	Lipid-lowering properties of TAK-475, a squalene synthase inhibitor, in vivo and in vitro. Br J Pharmacol. 2003 Jul;139(5):911-8.
REF 7	EP2306 [2-(4-biphenyl)-4-methyl-octahydro-1,4-benzoxazin-2-ol, hydrobromide], a novel squalene synthase inhibitor, reduces atherosclerosis in the c... J Pharmacol Exp Ther. 2007 Dec;323(3):794-804.

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