The pharmacological profile of ML3000: A new pyrrolizine derivative inhibiting the enzymes cyclo-oxygenase and 5-lipoxygenase

Tries, S.; Laufer, Stefan

doi:10.1163/156856001300248380

Cited by 42 publications

(27 citation statements)

References 3 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Studies from our laboratory also demonstrated the effectiveness of licofelone in various painful and inflammatory paradigms in experimental models (Singh et al 2005(Singh et al , 2006. Its gastroprotective, cardioprotective, analgesic and antipyretic effects have also been documented in several experimental models (Bias et al 2004;Tries et al 2002;Tries and Laufer 2001). Based on recent advancement in the understanding of both COX and LOX pathways, it is now speculated that prostaglandins and leukotrienes together may play an important role in the progression of inflammatory diseases (Fiorucci et al 2001) and therefore can be exploited to explore as new drug target to develop suitable drug candidate for neurological diseases including PD.…”

Section: Introductionmentioning

confidence: 83%

Licofelone attenuates MPTP-induced neuronal toxicity: behavioral, biochemical and cellular evidence

Gupta

Kumar

2010

Inflammopharmacol

View full text Add to dashboard Cite

Neuroinflammation and oxidative stress play critical role in the pathophysiology of neurodegenerative diseases including Parkinson's disease (PD). Recent reports indicate the beneficial effect of anti-inflammatory drugs in attenuating the progression of PD. Therefore, the present study is aimed to evaluate the possible role of licofelone, a dual COX/LOX-inhibitor against MPTP-induced neurotoxicity in mice. Administration of MPTP (40 mg/kg in divided doses of four injections of 10 mg/kg, i.p. each at 1 h interval) significantly impaired locomotor activity and induced catatonia, oxidative damage (elevated levels of lipid peroxidation, superoxide anion and nitrite, and decreased levels of non-protein thiols) as compared with vehicle-treated animals. Biochemical studies revealed significant alterations in mitochondrial enzyme complex activities (decreased complex-I activity and mitochondrial viability) and increased levels of caspase-3 and NF-κB/p65 as compared to vehicle treated group. Licofelone (2.5, 5 or 10 mg/kg/day, p.o.) treatment for 7 days significantly improved locomotor activity, attenuated the severity of catatonia, oxidative damage and restored mitochondrial enzyme complex activity as compared to MPTP-treated group. Licofelone treatment also attenuated the expression of apoptotic factor (caspase-3) and transcription factor (NF-κB/p65) as compared to MPTP-treated group. The findings of the present study suggest that licofelone (dual inhibitor of COX and LOX) represents a new class of anti-inflammatory agent which may provide a novel therapeutic alternative for the treatment and management of PD.

show abstract

Section: Introductionmentioning

confidence: 83%

Licofelone attenuates MPTP-induced neuronal toxicity: behavioral, biochemical and cellular evidence

Gupta

Kumar

2010

Inflammopharmacol

View full text Add to dashboard Cite

show abstract

“…Comparing the activity of compounds 13-18 with that of the parent compound 12, it was conceptualized that the acylation of the amino group at C6 with aromatic/electron withdrawing groups such as 2-chloroacetyl (13), benzoyl (16), 4-tolylsulfonyl (17), resulted in an observed improvement of the anti-inflammatory activity. On the other hand, the replacement of the chloro atom in compound 13 with a 4-methylpiperazinyl moiety or the cyclization of the side chain as in diazepine derivative 15 decreases the inflammatory activity ( Figure 5).…”

Section: In Vivo Biological Evaluationmentioning

confidence: 99%

“…Preparation of the COX-1, COX-2, and 5-LOX Protein and Ligands (12)(13)(14)(15)(16)(17)(18)(19) The protein structures were handled by using Accelrys Discovery Studio Visualize v4.1 software (Accelrys Inc., San Diego, CA, USA (2005)). The crystal structures of proteins were retrieved from Protein Data Bank (http://www.rscb.…”

Section: Molecular Docking Studymentioning

confidence: 99%

“…All water molecules were removed because the extra water molecules will mask the protein surface from the ligand. The three-dimensional structures (pdb format) of the ligands (12)(13)(14)(15)(16)(17)(18)(19) were constructed using Chem3D Ultra 8.0 software, then energetically minimized by using MOPAC with 100 iterations and minimum RMS gradient of 0.10. The AutoDock Tool (ADT) automatically computes Gasteiger charges to the 3D structures of the ligands.…”

Section: Molecular Docking Studymentioning

confidence: 99%

“…Interestingly, licofelone revealed anti-inflammatory and analgesic efficiency in asthmatic patients. Compared to other COX/ 5-LOX inhibitors which showed also good GIT tolerance, licofelone is the only COX/5-LOX inhibitor that showed an acceptable safety level in clinical use [17]. The replacement of the 4-chlorophenyl group at C5 in licofelone with a 5-chlorothiophen-2-yl moiety in compound 3 resulted in almost the same COX-1/5-LOX inhibitory activity [18].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Design, Synthesis, and Biological Evaluation of Some Novel Pyrrolizine Derivatives as COX Inhibitors with Anti-Inflammatory/Analgesic Activities and Low Ulcerogenic Liability

et al. 2016

View full text Add to dashboard Cite

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed anti-inflammatory and pain relief medications. However, their use is associated with many drawbacks, including mainly serious gastric and renal complications. In an attempt to circumvent these risks, a set of N-(4-bromophenyl)-7-cyano-6-substituted-H-pyrrolizine-5-carboxamide derivatives were designed, synthesized and evaluated as dual COX/5-LOX inhibitors. The structural elucidation, in vivo anti-inflammatory and analgesic activities using a carrageenan-induced rat paw edema model and hot plate assay, were performed, respectively. From the results obtained, it was found that the newly synthesized pyrrolizines exhibited IC 50 values in the range of 2.45-5.69 µM and 0.85-3.44 µM for COX-1 and COX-2, respectively. Interestingly, compounds 12, 13, 16 and 17 showed higher anti-inflammatory and analgesic activities compared to ibuprofen. Among these derivatives, compounds 16 and 19 displayed better safety profile than ibuprofen in acute ulcerogenicity and histopathological studies. Furthermore, the docking studies revealed that compound 17 fits nicely into COX-1 and COX-2 binding sites with the highest binding affinity, while compound 16 exerted the highest binding affinity for 5-LOX. In light of these findings, these novel pyrrolizine-5-carboxamide derivatives represent a promising scaffold for further development into potential dual COX/5-LOX inhibitors with safer gastric profile.

show abstract

Neue NSAR: Was bietet die Zukunft?

Laufer

2002

Pharmazie in unserer Zeit

View full text Add to dashboard Cite

The pharmacological profile of ML3000: A new pyrrolizine derivative inhibiting the enzymes cyclo-oxygenase and 5-lipoxygenase

Cited by 42 publications

References 3 publications

Licofelone attenuates MPTP-induced neuronal toxicity: behavioral, biochemical and cellular evidence

Licofelone attenuates MPTP-induced neuronal toxicity: behavioral, biochemical and cellular evidence

Design, Synthesis, and Biological Evaluation of Some Novel Pyrrolizine Derivatives as COX Inhibitors with Anti-Inflammatory/Analgesic Activities and Low Ulcerogenic Liability

Neue NSAR: Was bietet die Zukunft?

Contact Info

Product

Resources

About