A 2-methyleneoxetane analog of orlistat demonstrating inhibition of porcine pancreatic lipase

Dollinger, Lisa M.; Howell, Amy R.

doi:10.1016/s0960-894x(98)00140-1

Cited by 28 publications

(11 citation statements)

References 7 publications

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Section: Discussioncontrasting

confidence: 40%

“…Our investigation demonstrated that P-407 was not as potent an inhibitor of pancreatic lipase activity as that reported for orlistat (Hogan et al 1987;Dollinger & Howell 1998;Roche Technical Report 2003). The IC50 of orlistat ranged from approximately 0.2 to 0.8 M (Dollinger & Howell 1998), whereas the IC50 determined for P-407 in this study was 15.9 M; a greater than 20-fold difference. Additionally, using mice which were orally administered a standard lipid emulsion containing orlistat at a dose of 45 mg kg À1 , Han et al (2005) demonstrated that plasma triacylglycerol concentrations were reduced to comparable levels seen in this study using P-407 at a dose of 150 mg kg À1 .…”

Section: Discussioncontrasting

confidence: 40%

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Inhibition of pancreatic lipase by poloxamer 407 may provide an adjunct treatment strategy for weight loss

Johnston

Goldberg

2006

Journal of Pharmacy and Pharmacology

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This investigation was conducted to evaluate whether poloxamer 407 (P-407), a nonionic surface-active-agent that functions as a lipase inhibitor, could aid in weight loss by inactivating pancreatic lipase (PL) following oral administration to mice. Using a pH-titrimetric method, P-407 was evaluated for its ability to inhibit PL activity in-vitro. The palatability of drinking water containing P-407 (50 microM) was assessed in mice to determine whether inclusion of P-407 altered either the volume of water ingested, or the volume of urine produced, per day. P-407 at the same concentration was next evaluated for its potential to mediate weight loss over a one-month period in mice fed a high-fat diet. Faecal fat determinations and the potential for P-407 to lower plasma triacylglycerol concentrations following oral administration of a standard lipid emulsion were also conducted. P-407 was determined to have an IC50 of 15.9 microM in-vitro. Inclusion of P-407 in drinking water neither perturbed the daily volume of water ingested, nor the volume of urine produced. Over the course of one month, adult mice, which were fed the high-fat diet and treated with P-407, lost approximately 12.4+/-1.7% of their initial body weight, whereas, control mice fed the identical diet continued to slowly gain weight (7.3+/-0.5% of their initial body weight). The amount of total lipids excreted in the faeces of high-fat-fed, P-407-treated mice was approximately 45% greater than that observed for control mice eating the same diet. Lastly, plasma triacylglycerol concentrations following oral administration of the standard lipid emulsion containing P-407 were significantly lower than corresponding plasma triacylglycerol concentrations observed in mice administered the lipid emulsion alone. While not as potent as orlistat, P-407 may potentially represent an additional treatment strategy for weight loss, especially when combined with caloric restriction, regular exercise, and anti-obesity medications of other drug classes.

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Section: Discussioncontrasting

confidence: 40%

Section: Discussioncontrasting

confidence: 40%

Inhibition of pancreatic lipase by poloxamer 407 may provide an adjunct treatment strategy for weight loss

Johnston

Goldberg

2006

Journal of Pharmacy and Pharmacology

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“…The 2-methyleneoxetane analogue 40 of the anti-obesity drug, orlistat, could be prepared by methylenation in spite of the formamide group, albeit in low yield (Scheme 28). 58 Orlistat and compound 40 inhibit porcine pancreatic lipase to a similar degree.…”

Section: Petasis Reagentsmentioning

confidence: 89%

Titanium reagents for the alkylidenation of carboxylic acid and carbonic acid derivatives

Hartley

McKiernan

2002

J. Chem. Soc., Perkin Trans. 1

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“…We have previously shown that the 2-methyleneoxetane analog 6 (see Figure 1) of the anti-obesity drug, tetrahydrolipstatin (THL), was nearly as potent an inhibitor of porcine pancreatic lipase (PPL) as THL. 8 …”

mentioning

confidence: 99%

“…In addition, compounds trans - 5b and trans - 5d were methylenated to provide probes 11b and 11d , respectively, based on our earlier finding of the comparable activity of THL and its 2-methyleneoxetane analog in a PPL assay. 8 Thus, overall, 19 β-lactone-based probes were readily assembled from a single scaffold for evaluation by competitive ABPP.…”

mentioning

confidence: 99%

Combining cross-metathesis and activity-based protein profiling: New β-lactone motifs for targeting serine hydrolases

Camara

Kamat

Lasota

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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β-Lactones are a privileged structural motif as enzyme inhibitors and chemical probes, particularly for the inhibition of enzymes from the serine hydrolase class. Herein, we demonstrate that cross-metathesis (CM) of α-methylene-β-lactones offers rapid access to structurally diverse, previously unexplored β-lactones. Combining this approach with competitive activity-based protein profiling (ABPP) identified lead β-lactone inhibitors/probes for several serine hydrolases, including disease-associated enzymes and enzymes of uncharacterized function. The structural diversity afforded by the α-methylene-β-lactone scaffold thus expands the landscape of serine hydrolases that can be targeted by small-molecule inhibitors and should further the functional characterization of enzymes from this class through the optimization of target-selective probes.

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A 2-methyleneoxetane analog of orlistat demonstrating inhibition of porcine pancreatic lipase

Cited by 28 publications

References 7 publications

Inhibition of pancreatic lipase by poloxamer 407 may provide an adjunct treatment strategy for weight loss

Inhibition of pancreatic lipase by poloxamer 407 may provide an adjunct treatment strategy for weight loss

Titanium reagents for the alkylidenation of carboxylic acid and carbonic acid derivatives

Combining cross-metathesis and activity-based protein profiling: New β-lactone motifs for targeting serine hydrolases

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