Toru Minoshima

Potent Inhibitors of Acyl-CoA:Cholesterol Acyltransferase. 2. Structure−Activity Relationships of Novel N-(2,2-Dimethyl-2,3-dihydrobenzofuran-7-yl)amides

Novel N-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)amide derivatives 1 were synthesized and tested for their ability to inhibit rabbit small intestinal ACAT (acyl-CoA:cholesterol acyltransferase) and lower serum total cholesterol in cholesterol-fed rats. Among the synthesized compounds, N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)amide derivatives showed potent ACAT inhibitory activity. The synthesis and structure-activity relationships of these compounds are described. A methyl group at position 6 of the 2,3-dihydrobenzofuran moiety was important for potent ACAT inhibitory activity. In the series of N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl) amides, lipophilicity of the acyl moiety was necessary for the potent ACAT inhibitory activity. The highly lipophilic acid amides N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-2,2- dimethyldodecanamide (10) and 6-(4-chlorophenoxy)-N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-y l)-2,2-dimethyloctanamide (50) showed potent activity. Introduction of a dimethylamino group at position 5 of the 2,3-dihydrobenzofuran moiety resulted in highly potent activity. The most potent compound, N-[5-(dimethylamino)-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl ]-2,2-dimethyldodecanamide (13, TEI-6620), showed highly potent ACAT inhibitory activity (rabbit small intestine IC50 = 0.020 microM, rabbit liver IC50 = 0.009 microM), foam cell formation inhibitory activity (rat peritoneal macrophage IC50 = 0.030 microM), extremely potent serum cholesterol-lowering activity in cholesterol-fed rats (71% at a dose of 0.3 mg/kg/day po), and good bioavailability in fed dogs (Cmax = 2.68 microg/mL at 1 h, 10 mg/kg po).

The effect of a synthetic 7-thiaprostaglandin E1 derivative, TEI-6122, on monocyte chemoattractant protein-1 induced chemotaxis in THP-1 cells

1 The ability of various prostaglandins (PGs) to inhibit monocyte chemotaxis induced by monocyte chemoattractant protein‐1 (MCP‐1) was investigated with a human monocytic leukaemia cell line, THP‐1. Moreover, to investigate the mechanism of the inhibitory action of PGs the involvement of either intracellular adenosine 3″:5″‐cyclic monosphosphate (cyclic AMP) accumulation or intracellular Ca2+ mobilization was studied. 2 TEI‐6122, a synthetic 7‐thia‐PGE, derivative, inhibited chemotaxis of THP‐1 cells induced by MCP‐1 with an IC50 of 1.5 pM. Its inhibitory activity was 1000 fold more than that of PGE1 and PGE2 (IC50=2.8 nM and 0.9 nM, respectively), which were more potent than other PGs such as PGA1, PGA2, PGF2α and PGI2 (IC50≥1 μm). 3 With respect to the effect on intracellular cyclic AMP accumulation in THP‐1 cells, TEI‐6122 was as potent as PGEI and PGE2, which were approximately 100 to 1000 fold more potent than the other PGs such as PGA1, PGA2 and PGI2. The minimum concentration of TEI‐6122 required to increase intracellular cyclic AMP accumulation in THP‐1 cells was 1 nM. 4 TEI‐6122 and PGE1 (4 μm) transiently increased intracellular calcium levels in THP‐1 cells. When added prior to MCP‐1, both PGs partially suppressed the increased in Ca2+ caused by this cytokine. There were no significant differences between the activity of TEI‐6122 and PGEI in either respect. 5 It is concluded that TEI‐6122, a synthetic 7‐thia‐PGE, derivative is a much more potent inhibitor of MCP‐1‐induced THP‐1 cell chemotaxis than PGEI and PGE2 which are the best inhibitors among the natural PGs tested, while neither intracellular cyclic AMP accumulation nor effects on Ca2+ mobilization account for the extremely potent inhibitory activity of TEI‐6122. Thus, either a novel PGE2 receptor (EP receptor) or a novel intracellular signal transduction system may be involved in the extremely potent chemotaxis inhibitory activity of TEI‐6122.