Disease relevance of NO 1886

• The novel compound NO-1886 increases lipoprotein lipase activity with resulting elevation of high density lipoprotein cholesterol, and long-term administration inhibits atherogenesis in the coronary arteries of rats with experimental atherosclerosis [1].
• Moreover, total numbers of intestinal polyps in the groups receiving NO-1886 at 400 and 800 ppm were decreased to 48% and 42% of the control value, respectively [2].
• Correction of hypertriglyceridemia with low high-density lipoprotein cholesterol by the novel compound NO-1886, a lipoprotein lipase-promoting agent, in STZ-induced diabetic rats [3].
• RESULTS: Compared with chow-fed controls, a high-fat diet increased weight gain, an effect lessened by NO-1886 [weight gain (g): chow, 37 +/- 3, high-fat, 222 +/- 9; high-fat + NO-1886, 109 +/- 6, all groups differed p < 0.001] [4].
• Administration of NO-1886 (0.1 g/kg body weight/day) in the diet for 5 months significantly reduced atherosclerosis lesions and significantly increased plasma HDL-C and apolipoprotein A-I levels [5].

High impact information on NO 1886

• Administration of NO-1886 increased LPL enzyme mass in postheparin plasma and mRNA activity in epididymal adipose tissue, and it was concluded that the mode of action of this compound is stimulation of tissue LPL synthesis [1].
• These results indicate that suppression of serum lipid levels by increasing LPL activity may contribute to a reduction of intestinal polyp formation with Apc-deficiency, and NO-1886 and its derivatives could be useful as chemopreventive agents for colon cancer [2].
• We also found that NO-1886 suppressed cyclooxygenase-2 transcriptional promoter activity in a reporter gene assay and reduced cyclooxygenase-2 mRNA levels in the small intestine of Min mice [2].
• Meanwhile, a compound, NO-1886, has been shown to increase LPL mRNA and protein levels but not to possess PPARalpha and PPARgamma agonistic activity [2].
• The lipoprotein lipase activator, NO-1886, suppresses fat accumulation and insulin resistance in rats fed a high-fat diet [4].

Chemical compound and disease context of NO 1886

• These data suggest that NO-1886 may have a protective effect against Adriamycin-induced nephrosis with tubulointerstitial nephritis in rats by a modification of the plasma lipid disorder [6].
• The aim of this study was to ascertain whether NO-1886 improves fatty liver caused by high-fat feeding in streptozotocin (STZ)-induced diabetic rats [7].
• Overall, this study demonstrated that cachexia induced by B16 melanoma in mice was alleviated by the LPL activators bezafibrate and NO-1886, suggesting the involvement of the impaired LPL activity in the establishment of cachexia syndrome in mice bearing B16 melanoma [8].

Biological context of NO 1886

• A high-fat diet induced wholebody insulin resistance (clamp glucose infusion rate: 4.8 +/- 1.3 mg x kg(-1) x min(-1) vs 10.6 +/- 1.1 for the chow group, p < 0.01) with NO-1886 lessening this effect (8.3 +/- 0.5, p < 0.05 vs high-fat) [4].
• The aim of this study was to investigate the long-term effects of the lipoprotein lipase activator, NO-1886, on substrate utilisation, adiposity and insulin action in rats fed a high-fat diet [4].
• A novel series of quinazolines and 4(3H)-quinazolinones were prepared by cyclization of NO-1886 derivatives [9].
• Various analogs of NO-1886 were synthesized to study the structure-activity relationship of this hypolipidemic drug [9].
• In addition, the minor metabolic pathway in human liver was the hydrolysis of the amide bond of NO-1886 by a specific cytosolic esterase [10].

Anatomical context of NO 1886

• In summary, the results of our study indicate that compound NO-1886 increases LPL activity, causing an elevation in HDL levels, and that long-term administration of NO-1886 to rats with experimental atherosclerosis provides significant protection against the development of coronary artery lesions [1].
• In myocardium and skeletal muscle a high-fat diet lowered lipoprotein lipase activity, an effect lessened by NO-1886 [4].
• A similar pattern existed for fat accumulation [visceral fat (g): chow, 35.9 +/- 3.2; high-fat, 81.9 +/- 6.6; high-fat + NO-1886, 52.3 +/- 4.7, p < 0.01 high-fat vs the other groups] [4].
• NO-1886 attenuated smooth muscle contraction induced by the cumulative addition of CaCl(2) [11].
• NO-1886 decreases ectopic lipid deposition and protects pancreatic beta cells in diet-induced diabetic swine [12].

Associations of NO 1886 with other chemical compounds

• Following our report that administration of 4-diethoxyphosphorylmethyl-N-(4-bromo-2-cyanophenyl) benzamide (NO-1886) to rats elevated postheparin lipoprotein lipase (LPL) activity through an increase in the enzyme mass, we now investigate antiatherogenic effects of NO-1886 in cholesterol-fed New Zealand White rabbits [13].
• Eadie-Hofstee plots of phosphonate O-deethylation of NO-1886 in human liver microsomes showed a biphasic curve, indicating low- and high-K(m) components [10].
• However, NO-1886 affected steroid production from adrenocortical cells in rats, dogs, monkeys, and humans in in vitro studies [14].
• The results show that administration of NO-1886 attenuated aortic contraction induced by phenylephrine and/or a high K(+) environment, in both the presence and absence of aortic endothelium [11].
• The endothelium-dependent relaxation of the thoracic aorta caused by histamine was significantly impaired in old rats (% relaxation at 10(-5.5) M histamine: young rats 25.4+/-3.1%; old rats 14.1+/-1.9%, P < 0.01), an effect completely prevented by NO-1886 (old rats + NO-1886; 22.8+/-2.8%, P < 0.05 vs. old rats) [15].

Gene context of NO 1886

• Recombinant CYP3A4 and CYP2C8 expressed in baculovirus-infected insect cells and human lymphoblastoid cells exhibited a high activity for phosphonate O-deethylation of NO-1886 [10].
• Following additional culture for 24 hr in fresh medium without NO-1886, the expression of CYP3A4 mRNA was comparable to that in controls [16].
• However, the CYP3A5 mRNA level after exposure to 50 microM NO-1886 was not significantly increased [17].
• The expression levels of CYP1A2, CYP2B2, CYP2C12, and CYP2E1 mRNA in primary cultures of rat hepatocytes were not affected by exposure to NO-1886 at 2, 10, or 50 microM [16].
• A higher concentration (50 microM) of NO-1886 induced an increase in CYP2C8 mRNA and a decrease in CYP2C19 mRNA, and these changes continued after additional culture for 24 hr in fresh medium without NO-1886 [16].

Analytical, diagnostic and therapeutic context of NO 1886

• NO-1886 suppressed the body weight increase seen in the high-fat control group after the 8-week administration (585 +/- 39 vs 657 +/- 66 g, P < .05) [18].
• The AUC(0-)(t) for oral administration of NO-1886 (3 mg kg(-1)) was 4.23 micro g h ml(-1) and the bioavailability was 75% [19].
• NO-1886 decreased accumulation of visceral fat and suppressed the increase in body weight resulting from the ovariectomy [20].
• To address this problem, we examined the effect of NO-1886 on LPL activity in primary rat cell culture isolated from adipose and skeletal muscle tissue [21].
• The mRNA levels of human cytochrome P450 (CYP)2Cs and CYP3As in primary cultures of freshly isolated human hepatocytes were assessed after exposure to NO-1886 and rifampicin, a typical inducer of CYP3As. mRNA levels were analyzed by real-time RT-PCR using an ABI PRISM 7700 Sequence Detector system [16].

References