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Synthesis and evaluation of novel amide amino-β-lactam derivatives as cholesterol absorption inhibitors.

Dražić T, Sachdev V, Leopold C, Patankar JV, Malnar M, Hećimović S, Levak-Frank S, Habuš I, Kratky D - Bioorg. Med. Chem. (2015)

Bottom Line: In addition, we determined the activity of the three compounds to inhibit cholesterol absorption in vivo.Our results demonstrate that these compounds considerably reduce cholesterol concentrations in liver and small intestine of mice.Thus, our newly synthesized amide ezetimibe analogs are cholesterol absorption inhibitors in vitro and in vivo.

View Article: PubMed Central - PubMed

Affiliation: Ruđer Bošković Institute, Bijenička cesta 54, Zagreb, Croatia. Electronic address: tdrazic@irb.hr.

No MeSH data available.


Related in: MedlinePlus

Inhibition of cholesterol uptake in hNPC1L1/MDCKII cells for compounds (A) 5a (IC50 = 20 μM) and 5b (IC50 = 18 μM), (B) 5c (IC50 = 88 μM) and 5d (IC50 = 46 μM), (C) 5e (IC50 = 70 μM) and 5f (IC50 = 54 μM). The results are expressed as percentage of inhibition compared to untreated cells and represent mean ± SEM of three independent experiments. ∗p <0.05, ∗∗p <0.01, ∗∗∗p <0.001 determined by one-way ANOVA followed by Dunnett’s test.
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f0015: Inhibition of cholesterol uptake in hNPC1L1/MDCKII cells for compounds (A) 5a (IC50 = 20 μM) and 5b (IC50 = 18 μM), (B) 5c (IC50 = 88 μM) and 5d (IC50 = 46 μM), (C) 5e (IC50 = 70 μM) and 5f (IC50 = 54 μM). The results are expressed as percentage of inhibition compared to untreated cells and represent mean ± SEM of three independent experiments. ∗p <0.05, ∗∗p <0.01, ∗∗∗p <0.001 determined by one-way ANOVA followed by Dunnett’s test.

Mentions: Ezetimibe analogs 5a–f were tested for inhibition of cholesterol uptake in hNPC1L1/MDCKII cells (Fig. 3). The activity of ezetimibe 1 was determined previously (IC50 = 24 μM, maximum inhibition of 40% reached at ∼60 μM concentration).19 Analogs containing a cinnamoyl group (5a and b) had lowest IC50 values (20 and 18 μM, respectively), with maximum inhibition of ∼45% which was reached at 60 μM concentration (Fig. 3A), and their activity was comparable to ezetimibe 1. Compounds containing a benzyl substituent (5c and d) exhibited maximum inhibition of ∼40% with IC50 values of 88 and 46 μM, respectively (Fig. 3B). Derivatives with a phenyl group (5e and f) inhibited cholesterol uptake by 60–65% and had IC50 values of 70 and 54 μM, respectively (Fig. 3C). It is important to notice that derivatives containing 4-F-phenyl at the side chain displayed lower IC50 values than their phenyl couterparts in all three groups (Fig.3A–C). These results show that amide ezetimibe analogs 5a–f are potent inhibitors of cholesterol uptake in vitro.


Synthesis and evaluation of novel amide amino-β-lactam derivatives as cholesterol absorption inhibitors.

Dražić T, Sachdev V, Leopold C, Patankar JV, Malnar M, Hećimović S, Levak-Frank S, Habuš I, Kratky D - Bioorg. Med. Chem. (2015)

Inhibition of cholesterol uptake in hNPC1L1/MDCKII cells for compounds (A) 5a (IC50 = 20 μM) and 5b (IC50 = 18 μM), (B) 5c (IC50 = 88 μM) and 5d (IC50 = 46 μM), (C) 5e (IC50 = 70 μM) and 5f (IC50 = 54 μM). The results are expressed as percentage of inhibition compared to untreated cells and represent mean ± SEM of three independent experiments. ∗p <0.05, ∗∗p <0.01, ∗∗∗p <0.001 determined by one-way ANOVA followed by Dunnett’s test.
© Copyright Policy - CC BY
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4414353&req=5

f0015: Inhibition of cholesterol uptake in hNPC1L1/MDCKII cells for compounds (A) 5a (IC50 = 20 μM) and 5b (IC50 = 18 μM), (B) 5c (IC50 = 88 μM) and 5d (IC50 = 46 μM), (C) 5e (IC50 = 70 μM) and 5f (IC50 = 54 μM). The results are expressed as percentage of inhibition compared to untreated cells and represent mean ± SEM of three independent experiments. ∗p <0.05, ∗∗p <0.01, ∗∗∗p <0.001 determined by one-way ANOVA followed by Dunnett’s test.
Mentions: Ezetimibe analogs 5a–f were tested for inhibition of cholesterol uptake in hNPC1L1/MDCKII cells (Fig. 3). The activity of ezetimibe 1 was determined previously (IC50 = 24 μM, maximum inhibition of 40% reached at ∼60 μM concentration).19 Analogs containing a cinnamoyl group (5a and b) had lowest IC50 values (20 and 18 μM, respectively), with maximum inhibition of ∼45% which was reached at 60 μM concentration (Fig. 3A), and their activity was comparable to ezetimibe 1. Compounds containing a benzyl substituent (5c and d) exhibited maximum inhibition of ∼40% with IC50 values of 88 and 46 μM, respectively (Fig. 3B). Derivatives with a phenyl group (5e and f) inhibited cholesterol uptake by 60–65% and had IC50 values of 70 and 54 μM, respectively (Fig. 3C). It is important to notice that derivatives containing 4-F-phenyl at the side chain displayed lower IC50 values than their phenyl couterparts in all three groups (Fig.3A–C). These results show that amide ezetimibe analogs 5a–f are potent inhibitors of cholesterol uptake in vitro.

Bottom Line: In addition, we determined the activity of the three compounds to inhibit cholesterol absorption in vivo.Our results demonstrate that these compounds considerably reduce cholesterol concentrations in liver and small intestine of mice.Thus, our newly synthesized amide ezetimibe analogs are cholesterol absorption inhibitors in vitro and in vivo.

View Article: PubMed Central - PubMed

Affiliation: Ruđer Bošković Institute, Bijenička cesta 54, Zagreb, Croatia. Electronic address: tdrazic@irb.hr.

No MeSH data available.


Related in: MedlinePlus