A series of novel indoline derivatives with an ionizable moiety were synthesized to find a bioavailable acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor with antiperoxidative activity. [7-(2,2-Dimethylpropanamido)-4,6-dimethyl-1-octylindolin-5-yl]acetic acid hemisulfate (2, pactimibe sulfate) with low lipophilicity and high water solubility showed good oral absorption and inhibitory activity against foam cell formation in THP-1 cells exposed to acetyl-LDL after differentiation (IC50: 0.3 microM) and an antiperoxidative effect in LDL of hypercholesterolemic rabbits (IC50: 1.0 microM). 2 inhibited macrophage, hepatic, and intestinal ACAT activity (IC50: 1.9, 0.7, and 0.7 microM, respectively). Maximal plasma concentration after oral administration of 2 at 10 mg/kg was 0.9 microg/mL in rats, 3.0 microg/mL in rabbits, and 11.2 microg/mL in dogs. Repeated administration of 2 lowered plasma LDL/VLDL cholesterol in hypercholesterolemic rabbits at 1 mg/kg/day, rats and dogs at 3 mg/kg/day, and in normocholesterolemic hamsters at 3 mg/kg/day. 2 is a promising candidate for antihyperlipidemic and antiatherosclerotic drugs.