K-604 (hydrochloride)

K-604 is an inhibitor of acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1; IC₅₀ = 0.45 µM).¹ It is selective for ACAT-1 over ACAT-2 (IC₅₀ = 102.85 µM). K-604 reduces foaming of J774 macrophages (IC₅₀ = 0.026 µM) and reduces cholesterol esterification in monocyte-derived macrophages (IC₅₀ = 0.068 µM).^1,2 It decreases lipid-accumulation areas in the aortic arch in atherosclerosis-susceptible Bio F1B hamsters fed a high-fat and high-cholesterol diet when administered at a dose of 10 mg/kg and reduces plasma total cholesterol levels in the same model at 10 and 30 mg/kg.¹ K-604 also increases the LC3-II-to-LC3-I ratio, a marker of autophagosome formation, in Neuro2a (N2a) mouse neuroblastoma cells when used at concentrations of 0.1 and 1 µM.³ It decreases wild-type and mutant P301L-tau levels in N2a cells overexpressing these proteins but does not affect endogenous tau levels. Intranasal administration of K-604 (105 µg/animal) reduces the level of brain cholesteryl esters in mice.³

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1. Shibuya, K., Kawamine, K., Ozaki, C., et al. Discovery of clinical candidate 2-(4-(2-((1 H-benzo[d]imidazol-2-yl)thio)ethyl)piperazin-1-yl)-N-(6-methyl-2,4-bis(methylthio)pyridin-3-yl)acetamide hydrochloride [K^-604], an aqueous-soluble acyl-CoA:Cholesterol O-acyltransferase-1 inhibitor. J. Med. Chem. 61(23), 10635-10650 (2018).

2. Ikenoya, M., Yoshinaka, Y., Kobayashi, H., et al. A selective ACAT-1 inhibitor, K^-604, suppresses fatty streak lesions in fat-fed hamsters without affecting plasma cholesterol levels. Atherosclerosis 191(2), 290-297 (2007).

3. Shibuya, Y., Niu, Z., Bryleva, E.Y., et al. Acyl-coenzyme A:cholesterol acyltransferase 1 blockage enhances autophagy in the neurons of triple transgenic Alzheimer’s disease mouse and reduces human P301L-tau content at the presymptomatic stage. Neurobiol. Aging 36(7), 2248-2259 (2015).