Reference - Detail
| RRC ID | 72386 |
|---|---|
| Author | Ohishi K, Aiyama R, Hatano H, Yoshida Y, Wada Y, Yokoi W, Sawada H, Watanabe T, Yokokura T. |
| Title | Structure-activity relationships of N-(3,5-dimethoxy-4-n-octyloxycinnamoyl)-N'-(3,4-dimethylphenyl)piperazine and analogues as inhibitors of acyl-CoA: cholesterol O-acyltransferase. |
| Journal | Chem Pharm Bull (Tokyo) |
| Abstract |
A novel series of acyl-CoA: cholesterol O-acyltransferase (ACAT) inhibitors were synthesized from a lead compound, 1-(4-hydroxy-3-methoxyphenyl)-7-phenylhept-1-en-3-one (1, Yakuchinone B) through a modification of three regions (A, B, C) in the molecule. In this study, the compounds prepared were tested for in vitro inhibitory activity on microsomal ACAT from the liver of rats and for in vivo hypocholesterolemic activity in rats given a high cholesterol diet. N-(3,5-Dimethoxy-4-n-octyloxycinnamoyl)-N'-(3,4-dimethylphenyl)piperazine (45), which belongs to the amide compounds, has finally been discovered. Compound 45 inhibited rat hepatic ACAT in a more striking manner than CI-976, an amide compound ACAT inhibitor, and it exhibited a high level of hypocholesterolemic activity in vivo. Since 45 strongly inhibited both microsomal ACAT prepared from HepG2 (a cell line derived from human hepatocarcinoma) and Caco2 (a cell line derived from human colon adenocarcinoma), there is speculation that 45 might have the ability to inhibit ACAT in both the human intestine and liver independent of the difference in the distribution of ACAT isozymes. On the other hand, 45 did not induce adrenotoxicity in subacute toxicity studies in rats. These results suggest that it has promise for development as a new therapeutic agent for hypercholesterolemia and atherosclerosis. |
| Volume | 49(7) |
| Pages | 830-9 |
| Published | 2001-7-1 |
| DOI | 10.1248/cpb.49.830 |
| PMID | 11456087 |
| MeSH | Animals Anticholesteremic Agents / chemical synthesis* Anticholesteremic Agents / pharmacology* Caco-2 Cells Cholesterol / blood Cholesterol, Dietary / metabolism Cinnamates / chemical synthesis* Cinnamates / pharmacology* Enzyme Inhibitors / chemical synthesis* Enzyme Inhibitors / pharmacology* Humans Liver Neoplasms, Experimental / metabolism Male Microsomes, Liver / drug effects Microsomes, Liver / enzymology Piperazines / chemical synthesis* Piperazines / pharmacology* Rats Rats, Sprague-Dawley Sterol O-Acyltransferase / antagonists & inhibitors* Structure-Activity Relationship Tumor Cells, Cultured |
| IF | 1.416 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | Patent(IFI CLAIMS) |
| Total number of mentions | 1 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | CAC0-2(RCB0988) Hep G2(RCB0459) |