The Experts below are selected from a list of 417 Experts worldwide ranked by ideXlab platform
Rhonda M Jenkins - One of the best experts on this subject based on the ideXlab platform.
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effect of the acyl coa Cholesterol Acyltransferase Inhibitor dup 128 on Cholesterol absorption and serum Cholesterol in humans
Clinical Pharmacology & Therapeutics, 1994Co-Authors: James W Hainer, Greg J Terry, Jill M Connell, Hanna Zyruk, Rhonda M JenkinsAbstract:Intestinal Cholesterol esterification by the enzyme acyl-CoA:Cholesterol Acyltransferase (ACAT) is a presumed prerequisite for Cholesterol absorption. We evaluated the effect of a potent, poorly absorbed ACAT Inhibitor (DuP 128: N′-(2,4-difluorophenyl)-N-[5-(4,5-diphenyl-lH-imidazol-2-ylthio)pentyl]-N-heptylurea) on Cholesterol absorption in a randomized trial. Thirty subjects received DuP 128 for 7 weeks, 10 each at 900 mg per day, 1800 mg per day, and 3600 mg per day;six subjects received placebo; and nine subjects received 1 gm neomycin twice a day. Cholesterol absorption determinations used a continuous dual isotope 14C-Cholesterol and 3H-beta sitosterol method. DuP 128 (pooled doses) induced at 14.4% ± 11.4% reduction in Cholesterol absorption (p < 0.05 versus placebo): 17.6% ± 8.4% at 900 mg, 9.1% ± 11.4% at 1800 mg, and 17.1% ± 12.9% at 3600 mg. Neomycin induced a 26.4% ± 10.7% reduction (p < 0.01). After 6 weeks, neomycin reduced serum total and low-density lipoprotein Cholesterol by 22.4% ± 9.2% and 24.0% ± 11.6%, respectively (p < 0.01 versus placebo). DuP 128 induced reductions of 3.9% ± 11% (difference not significant) and 4.95% ± 14.3% (p = 0.05). ACAT Inhibitors limit Cholesterol absorption in humans; however, the magnitude of the effect, as exemplified by DuP 128, is small. Clinical Pharmacology and Therapeutics (1994) 56, 65–74; doi:10.1038/clpt.1994.102
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effect of the acyl coa Cholesterol Acyltransferase Inhibitor dup 128 on Cholesterol absorption and serum Cholesterol in humans
Clinical Pharmacology & Therapeutics, 1994Co-Authors: James W Hainer, Greg J Terry, Jill M Connell, Hanna Zyruk, Rhonda M JenkinsAbstract:Intestinal Cholesterol esterification by the enzyme acyl-CoA:Cholesterol Acyltransferase (ACAT) is a presumed prerequisite for Cholesterol absorption. We evaluated the effect of a potent, poorly absorbed ACAT Inhibitor (DuP 128: N'-(2,4-difluorophenyl)-N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pe ntyl]- N-heptylurea) on Cholesterol absorption in a randomized trial. Thirty subjects received DuP 128 for 7 weeks, 10 each at 900 mg per day, 1800 mg per day, and 3600 mg per day; six subjects received placebo; and nine subjects received 1 gm neomycin twice a day. Cholesterol absorption determinations used a continuous dual isotope 14C-Cholesterol and 3H-beta sitosterol method. DuP 128 (pooled doses) induced at 14.4% +/- 11.4% reduction in Cholesterol absorption (p < 0.05 versus placebo): 17.6% +/- 8.4% at 900 mg, 9.1% +/- 11.4% at 1800 mg, and 17.1% +/- 12.9% at 3600 mg. Neomycin induced a 26.4% +/- 10.7% reduction (p < 0.01). After 6 weeks, neomycin reduced serum total and low-density lipoprotein Cholesterol by 22.4% +/- 9.2% and 24.0% +/- 11.6%, respectively (p < 0.01 versus placebo). DuP 128 induced reductions of 3.9% +/- 11% (difference not significant) and 4.95% +/- 14.3% (p = 0.05). ACAT Inhibitors limit Cholesterol absorption in humans; however, the magnitude of the effect, as exemplified by DuP 128, is small.
Hiroaki Shirahase - One of the best experts on this subject based on the ideXlab platform.
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novel acyl coa Cholesterol Acyltransferase Inhibitor indoline based sulfamide derivatives with low lipophilicity and protein binding ratio
ChemInform, 2011Co-Authors: Kenji Takahashi, Masaru Ohta, Yoshimichi Shoji, Masayasu Kasai, Kazuyoshi Kunishiro, Tomohiro Miike, Mamoru Kanda, Hiroaki ShirahaseAbstract:Starting from N(1-acetyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide a series of novel indoline-based sulfamide derivatives are synthesized.
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novel acyl coa Cholesterol Acyltransferase Inhibitor indoline based sulfamide derivatives with low lipophilicity and protein binding ratio
Chemical & Pharmaceutical Bulletin, 2010Co-Authors: Kenji Takahashi, Masaru Ohta, Yoshimichi Shoji, Masayasu Kasai, Kazuyoshi Kunishiro, Tomohiro Miike, Mamoru Kanda, Hiroaki ShirahaseAbstract:To find a novel acyl-CoA: Cholesterol Acyltransferase Inhibitor, a series of sulfamide derivatives were synthesized and evaluated. Compound 1d, in which carboxymethyl moiety at the 5-position of Pactimibe was replaced by a sulfamoylamino group, showed 150-fold more potent anti-foam cell formation activity (IC(50): 0.02 microM), 1.6-fold higher log D(7.0) (4.63), and a slightly lower protein binding ratio (93.2%) than Pactimibe. Compound 1i, in which the octyl chain at the 1-position in 1d was replaced by an ethoxyethyl, showed markedly low log D(7.0) (1.73) and maintained 3-fold higher anti-foam cell formation activity (IC(50): 1.0 microM), than Pactimibe. The plasma protein binding ratio (PBR) of 1i was much lower than that of Pactimibe (62.5% vs. 98.1%), and its partition ratio to the rabbit atherosclerotic aorta after oral administration was higher than that of Pactimibe. Compound 1i at 10 microM markedly inhibited Cholesterol esterification in atherosclerotic rabbit aortas even when incubated with serum, while Pactimibe had little effect probably due to its high PBR. In conclusion, compound 1i is expected to more efficiently inhibit the progression of atherosclerosis than Pactimibe.
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novel indoline based acyl coa Cholesterol Acyltransferase Inhibitor effects of introducing a methanesulfonamide group on physicochemical properties and biological activities
Bioorganic & Medicinal Chemistry, 2009Co-Authors: Yoshimichi Shoji, Kenji Takahashi, Masaru Ohta, Masayasu Kasai, Kazuyoshi Kunishiro, Mamoru Kanda, Satoko Yogai, Yasuo Takeuchi, Hiroaki ShirahaseAbstract:A novel series of indoline-based acyl-CoA: Cholesterol Acyltransferase (ACAT) Inhibitors with a methanesulfonamide group at the 5-position were synthesized and their lipophilicity and biological activities were evaluated. Hepatic ACAT Inhibitory and anti-foam cell formation activity increased dependent on lipophilicity of derivatives with various alkyl chains at the 1-position. The logD(7.0)-biological activity curve of the derivatives with a methanesulfonamide group shifted leftward compared to that of Pactimibe derivatives with a carboxymethyl group, and derivatives with no substituent, suggesting that a methanesulfonamide group plays an important role in the interaction with ACAT protein. Among derivatives, N-(1-ethyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (1b) had about twofold lower logD(7.0) than Pactimibe, while it showed twofold higher hepatic ACAT inhibition than and the same anti-foam cell formation as Pactimibe, respectively. The C(max) of 1b (10mg/kg, po) was higher than that of Pactimibe in rats. The plasma protein binding ratio of 1b was lower than that of Pactimibe: 64.8% and 97.9%, respectively. Compound 1b showed greater Inhibitory effects on hepatic Cholesterol secretion in mice than Pactimibe. In conclusion, the introduction of a methanesulfonamide group is effective to design less lipophilic, more efficacious and more bioavailable indoline-based ACAT Inhibitors than previous indoline-based Inhibitors.
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novel indoline based acyl coa Cholesterol Acyltransferase Inhibitor with antiperoxidative activity improvement of physicochemical properties and biological activities by introduction of carboxylic acid
Journal of Medicinal Chemistry, 2008Co-Authors: Kenji Takahashi, Masaru Ohta, Yoshimichi Shoji, Masayasu Kasai, Kazuyoshi Kunishiro, Mamoru Kanda, Kazuyoshi Kurahashi, Hiroaki ShirahaseAbstract: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 μM) and an antiperoxidative effect in LDL of hyperCholesterolemic rabbits (IC50: 1.0 μM). 2 inhibited macrophage, hepatic, and intestinal ACAT activity (IC50: 1.9, 0.7, and 0.7 μM, respectively). Maximal plasma concentration after oral administration of 2 at 10 mg/kg was 0.9 μg/mL in rats, 3.0 μg/mL in rabbits, and 11.2 μg/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 ...
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Inhibitory effect of acyl coa Cholesterol Acyltransferase Inhibitor low density lipoprotein complex on experimental atherosclerosis
Biological & Pharmaceutical Bulletin, 2003Co-Authors: Yoshihiko Tauchi, Hiroaki Shirahase, Akihisa Yoshimi, Juichi Sato, Keiji Ito, Kazuhiro MorimotoAbstract:KV-2920 is a novel acyl-CoA: Cholesterol Acyltransferase (ACAT) Inhibitor. To confirm the efficacy of KV-2920-low density lipoprotein (LDL) complex (KV-LDL complex) as a drug-carrier complex on experimental atherosclerosis, we examined its Inhibitory effects in vitro and in vivo. LDL was isolated from human plasma and the KV-LDL complex was prepared by incubation in the presence of Celite 545. The complex contained about 800 mol KV-2920 in 1 mol LDL. The Cholesterol levels in the serum and aorta of atherogenic mice after 14 weeks of feeding were significantly higher than those of nonatherogenic mice. With the intravenous injection of KV-LDL complex, although the Cholesterol levels in the serum were not influenced, the level of Cholesterol ester in the aorta of atherogenic mice was significantly reduced. The concentration of Cholesterol ester in the macrophages derived from ICR mice was predominantly increased by incubation with LDL for 48 h, this increase was significantly inhibited by incubation with KV-LDL complex. Moreover, the complex also inhibited the increase of Cholesterol ester in macrophages following incubation with oxidized LDL. These findings suggest that KV-LDL complex inhibits the foam cell formation of macrophages though action of KV-2920 as an ACAT Inhibitor, and prevents the accumulation of Cholesterol ester in the aorta of atherogenic mice. Therefore, KV-LDL complex may be useful as a drug-carrier complex in antiatherosclerotic therapy.
Tsun Chang - One of the best experts on this subject based on the ideXlab platform.
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biodisposition studies with the acyl coenzyme a Cholesterol Acyltransferase Inhibitor 2 2 dimethyl n 2 4 6 trimethoxyphenyl dodecanamide ci 976
Drug Metabolism and Disposition, 1993Co-Authors: Thomas F Woolf, Ann E Black, Y Y Shum, W Mcnally, H Lee, Tsun ChangAbstract:2,2-Dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide, CI-976, is a newly developed fatty acid anilide being evaluated as a plasma lipid regulator and antiatherosclerotic agent. Disposition studies with CI-976 were conducted in rats and monkeys. In rats, CI-976 (suspension, 50 mg/kg) was approximately 30% bioavailable, with 46% of the administered radioactivity recovered in urine suggesting presystemic metabolism. The intravenous elimination half-life of CI-976 in rats was approximately 8 hr. Radioactivity derived from [14C]CI-976 was almost completely recovered in rats after either oral or intravenous administration. In bile duct-cannulated rats receiving either an oral or intravenous dose, biliary excretion was the major route of drug-derived radioactivity elimination. There was no evidence for unchanged drug in urine or bile. In monkeys, 13% urinary recovery and 5% bioavailability was achieved after a single 50 mg/kg suspension dose. Similar values were obtained following a 250 mg/kg dose. Monkeys displayed a CI-976 elimination half-life of 0.6 hr after a 2 mg/kg intravenous dose. No unchanged drug was excreted in urine. In summary, CI-976 exhibits moderate absorption and bioavailability in the rat, but lower absorption and bioavailability in monkey. A special difference in CI-976 elimination half-life was observed consistent with in vitro metabolism results.
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metabolism of the acyl coa Cholesterol Acyltransferase Inhibitor 2 2 dimethyl n 2 4 6 trimethoxyphenyl dodecanamide in rat and monkey omega beta oxidation pathway
Drug Metabolism and Disposition, 1991Co-Authors: Thomas F Woolf, Ann E Black, Susan M Bjorge, Ann Holmes, Tsun ChangAbstract:2,2-Dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide (CI-976) is a newly developed hypoCholesterolemic agent. In pharmacokinetic studies, CI-976 was found to have a much shorter elimination half-life in monkey (0.6 hr) compared to rat (8 hr). Radioactivity analysis of biological samples from rats and monkeys administered [14C]CI-976 either iv or orally showed CI-976 to be extensively metabolized to a single major common metabolite. This metabolite was isolated and its structure determined by GC/MS, LC/MS, and NMR spectroscopy as a 6-carbon chain-shortened carboxylic acid derivative, 5,5-dimethyl-6-oxo-6-[(2,4,6-trimethoxyphenyl)amino]-hexanoic acid. A potential pathway leading to this carboxylic acid derivative may involve initial omega-oxidation followed by beta-oxidation. A potential species difference in omega-/beta-oxidative biotransformation capabilities appears to exist.
James W Hainer - One of the best experts on this subject based on the ideXlab platform.
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effect of the acyl coa Cholesterol Acyltransferase Inhibitor dup 128 on Cholesterol absorption and serum Cholesterol in humans
Clinical Pharmacology & Therapeutics, 1994Co-Authors: James W Hainer, Greg J Terry, Jill M Connell, Hanna Zyruk, Rhonda M JenkinsAbstract:Intestinal Cholesterol esterification by the enzyme acyl-CoA:Cholesterol Acyltransferase (ACAT) is a presumed prerequisite for Cholesterol absorption. We evaluated the effect of a potent, poorly absorbed ACAT Inhibitor (DuP 128: N′-(2,4-difluorophenyl)-N-[5-(4,5-diphenyl-lH-imidazol-2-ylthio)pentyl]-N-heptylurea) on Cholesterol absorption in a randomized trial. Thirty subjects received DuP 128 for 7 weeks, 10 each at 900 mg per day, 1800 mg per day, and 3600 mg per day;six subjects received placebo; and nine subjects received 1 gm neomycin twice a day. Cholesterol absorption determinations used a continuous dual isotope 14C-Cholesterol and 3H-beta sitosterol method. DuP 128 (pooled doses) induced at 14.4% ± 11.4% reduction in Cholesterol absorption (p < 0.05 versus placebo): 17.6% ± 8.4% at 900 mg, 9.1% ± 11.4% at 1800 mg, and 17.1% ± 12.9% at 3600 mg. Neomycin induced a 26.4% ± 10.7% reduction (p < 0.01). After 6 weeks, neomycin reduced serum total and low-density lipoprotein Cholesterol by 22.4% ± 9.2% and 24.0% ± 11.6%, respectively (p < 0.01 versus placebo). DuP 128 induced reductions of 3.9% ± 11% (difference not significant) and 4.95% ± 14.3% (p = 0.05). ACAT Inhibitors limit Cholesterol absorption in humans; however, the magnitude of the effect, as exemplified by DuP 128, is small. Clinical Pharmacology and Therapeutics (1994) 56, 65–74; doi:10.1038/clpt.1994.102
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effect of the acyl coa Cholesterol Acyltransferase Inhibitor dup 128 on Cholesterol absorption and serum Cholesterol in humans
Clinical Pharmacology & Therapeutics, 1994Co-Authors: James W Hainer, Greg J Terry, Jill M Connell, Hanna Zyruk, Rhonda M JenkinsAbstract:Intestinal Cholesterol esterification by the enzyme acyl-CoA:Cholesterol Acyltransferase (ACAT) is a presumed prerequisite for Cholesterol absorption. We evaluated the effect of a potent, poorly absorbed ACAT Inhibitor (DuP 128: N'-(2,4-difluorophenyl)-N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pe ntyl]- N-heptylurea) on Cholesterol absorption in a randomized trial. Thirty subjects received DuP 128 for 7 weeks, 10 each at 900 mg per day, 1800 mg per day, and 3600 mg per day; six subjects received placebo; and nine subjects received 1 gm neomycin twice a day. Cholesterol absorption determinations used a continuous dual isotope 14C-Cholesterol and 3H-beta sitosterol method. DuP 128 (pooled doses) induced at 14.4% +/- 11.4% reduction in Cholesterol absorption (p < 0.05 versus placebo): 17.6% +/- 8.4% at 900 mg, 9.1% +/- 11.4% at 1800 mg, and 17.1% +/- 12.9% at 3600 mg. Neomycin induced a 26.4% +/- 10.7% reduction (p < 0.01). After 6 weeks, neomycin reduced serum total and low-density lipoprotein Cholesterol by 22.4% +/- 9.2% and 24.0% +/- 11.6%, respectively (p < 0.01 versus placebo). DuP 128 induced reductions of 3.9% +/- 11% (difference not significant) and 4.95% +/- 14.3% (p = 0.05). ACAT Inhibitors limit Cholesterol absorption in humans; however, the magnitude of the effect, as exemplified by DuP 128, is small.
Kenji Takahashi - One of the best experts on this subject based on the ideXlab platform.
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novel acyl coa Cholesterol Acyltransferase Inhibitor indoline based sulfamide derivatives with low lipophilicity and protein binding ratio
ChemInform, 2011Co-Authors: Kenji Takahashi, Masaru Ohta, Yoshimichi Shoji, Masayasu Kasai, Kazuyoshi Kunishiro, Tomohiro Miike, Mamoru Kanda, Hiroaki ShirahaseAbstract:Starting from N(1-acetyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide a series of novel indoline-based sulfamide derivatives are synthesized.
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novel acyl coa Cholesterol Acyltransferase Inhibitor indoline based sulfamide derivatives with low lipophilicity and protein binding ratio
Chemical & Pharmaceutical Bulletin, 2010Co-Authors: Kenji Takahashi, Masaru Ohta, Yoshimichi Shoji, Masayasu Kasai, Kazuyoshi Kunishiro, Tomohiro Miike, Mamoru Kanda, Hiroaki ShirahaseAbstract:To find a novel acyl-CoA: Cholesterol Acyltransferase Inhibitor, a series of sulfamide derivatives were synthesized and evaluated. Compound 1d, in which carboxymethyl moiety at the 5-position of Pactimibe was replaced by a sulfamoylamino group, showed 150-fold more potent anti-foam cell formation activity (IC(50): 0.02 microM), 1.6-fold higher log D(7.0) (4.63), and a slightly lower protein binding ratio (93.2%) than Pactimibe. Compound 1i, in which the octyl chain at the 1-position in 1d was replaced by an ethoxyethyl, showed markedly low log D(7.0) (1.73) and maintained 3-fold higher anti-foam cell formation activity (IC(50): 1.0 microM), than Pactimibe. The plasma protein binding ratio (PBR) of 1i was much lower than that of Pactimibe (62.5% vs. 98.1%), and its partition ratio to the rabbit atherosclerotic aorta after oral administration was higher than that of Pactimibe. Compound 1i at 10 microM markedly inhibited Cholesterol esterification in atherosclerotic rabbit aortas even when incubated with serum, while Pactimibe had little effect probably due to its high PBR. In conclusion, compound 1i is expected to more efficiently inhibit the progression of atherosclerosis than Pactimibe.
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novel indoline based acyl coa Cholesterol Acyltransferase Inhibitor effects of introducing a methanesulfonamide group on physicochemical properties and biological activities
Bioorganic & Medicinal Chemistry, 2009Co-Authors: Yoshimichi Shoji, Kenji Takahashi, Masaru Ohta, Masayasu Kasai, Kazuyoshi Kunishiro, Mamoru Kanda, Satoko Yogai, Yasuo Takeuchi, Hiroaki ShirahaseAbstract:A novel series of indoline-based acyl-CoA: Cholesterol Acyltransferase (ACAT) Inhibitors with a methanesulfonamide group at the 5-position were synthesized and their lipophilicity and biological activities were evaluated. Hepatic ACAT Inhibitory and anti-foam cell formation activity increased dependent on lipophilicity of derivatives with various alkyl chains at the 1-position. The logD(7.0)-biological activity curve of the derivatives with a methanesulfonamide group shifted leftward compared to that of Pactimibe derivatives with a carboxymethyl group, and derivatives with no substituent, suggesting that a methanesulfonamide group plays an important role in the interaction with ACAT protein. Among derivatives, N-(1-ethyl-5-methanesulfonylamino-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (1b) had about twofold lower logD(7.0) than Pactimibe, while it showed twofold higher hepatic ACAT inhibition than and the same anti-foam cell formation as Pactimibe, respectively. The C(max) of 1b (10mg/kg, po) was higher than that of Pactimibe in rats. The plasma protein binding ratio of 1b was lower than that of Pactimibe: 64.8% and 97.9%, respectively. Compound 1b showed greater Inhibitory effects on hepatic Cholesterol secretion in mice than Pactimibe. In conclusion, the introduction of a methanesulfonamide group is effective to design less lipophilic, more efficacious and more bioavailable indoline-based ACAT Inhibitors than previous indoline-based Inhibitors.
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novel indoline based acyl coa Cholesterol Acyltransferase Inhibitor with antiperoxidative activity improvement of physicochemical properties and biological activities by introduction of carboxylic acid
Journal of Medicinal Chemistry, 2008Co-Authors: Kenji Takahashi, Masaru Ohta, Yoshimichi Shoji, Masayasu Kasai, Kazuyoshi Kunishiro, Mamoru Kanda, Kazuyoshi Kurahashi, Hiroaki ShirahaseAbstract: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 μM) and an antiperoxidative effect in LDL of hyperCholesterolemic rabbits (IC50: 1.0 μM). 2 inhibited macrophage, hepatic, and intestinal ACAT activity (IC50: 1.9, 0.7, and 0.7 μM, respectively). Maximal plasma concentration after oral administration of 2 at 10 mg/kg was 0.9 μg/mL in rats, 3.0 μg/mL in rabbits, and 11.2 μg/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 ...
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bioavailable acyl coa Cholesterol Acyltransferase Inhibitor with anti peroxidative activity synthesis and biological activity of novel indolinyl amide and urea derivatives
ChemInform, 2000Co-Authors: Shoji Kamiya, Kenji Takahashi, Masayasu Kasai, Mamoru Kanda, Hiroaki Shirahase, Akihisa Yoshimi, Shohei Nakamura, Hiroshi Matsui, Kazuyoshi KurahashiAbstract:We synthesized a series of indoline derivatives with an amide or urea moiety and examined their Inhibitory effects on acyl-CoA : Cholesterol Acyltransferase (ACAT) activity, lipid-peroxidation and serum Cholesterol levels in experimental animals. Among the derivatives synthesized, a series of N-(1-alkyl-4, 6-dimethylindolin-7-yl)-2, 2-dimethylpropanamides potently inhibited rabbit intestinal ACAT activity and lipid-peroxidation of rat brain homogenate. The effect on ACAT activity was related to the length of the alkyl chain at the 1-position of indoline. N-(4, 6-Dimethyl-1-octylindolin-7-yl)-2, 2-dimethylpropanamide hydrochloride (55) showed Inhibitory effects on intestinal and hepatic ACAT activity slightly weaker than those of YM-750, and an Inhibitory effect on low density lipoprotein (LDL)-peroxidation similar to that of probucol. Compound 55 also reduced serum Cholesterol at 10mg/kg/d in hyperlipidemic rats and 20 mg/kg/d in normolipidemic hamsters. The plasma concentration of 55 reached 716ng/ml in dogs (10mg/kg, p.o.), which is an effect concentration against hepatic ACAT activity and LDL-peroxidation. In conclusion, compound 55 is a novel bioavailable ACAT Inhibitor with anti-peroxidative activity and is thus a promising anti-atherosclerotic and anti-hyperlipidemic drug. Indoline proved to be a useful pharmacophore for molecular design of new anti-peroxidative drugs.