Substituted Isoxazoles as Potent Inhibitors of p38 MAP Kinase

Laufer, Stefan; Margutti, Simona; Fritz, Martina D.

doi:10.1002/cmdc.200500025

Cited by 34 publications

(33 citation statements)

References 43 publications

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“…The compound 4-[3-(4-fluorophenyl)isoxazol-4-yl]pyridine displayed a promising anti-inflammatory activity, by suppressing cytokine release, lowering the affinity for cytochorme P450 and showing a decreased in the IC 50 toward isolated p38 MAPK [9]. Another heterocycle with a potential to serve as an anti-inflammatory molecule is the 4,5-dihydroisoxazole, or isoxazoline.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of 3-(3-chloro-phenyl)-5-(4-pyridyl)-4,5-dihydroisoxazole as a Novel Anti-Inflammatory Drug Candidate

et al. 2012

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Background3-(3-chloro-phenyl)-5-(4-pyridyl)-4,5-dihydroisoxazole (DIC) is a five-membered heterocyclic compound containing a N-O bond. The anti-inflammatory effects of this compound were studied both in vitro and in vivo.Principal FindingsDIC effectively decreased TNF-α and IL-6 release from LPS-stimulated macrophages in a dose dependent manner. DIC diminished the levels of COX-2 with subsequent inhibition of PGE2 production. DIC also compromised HMGB1 translocation from the nucleus to the cytoplasm. Moreover, DIC prevented the nuclear translocation of NF-κB and inhibited the MAPK pathway. In vivo, DIC inhibited migration of neutrophils to the peritoneal cavity of mice.ConclusionsThis study presents the potential utilization of a synthetic compound, as a lead for the development of novel anti-inflammatory drugs.

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Section: Introductionmentioning

confidence: 99%

Evaluation of 3-(3-chloro-phenyl)-5-(4-pyridyl)-4,5-dihydroisoxazole as a Novel Anti-Inflammatory Drug Candidate

et al. 2012

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“…Hepatic toxicity was ascribed to the pyridinyl imidazole derivatives [4]. Hence, subsequent studies were carried out with a broader set of with anticytokine scaffolds more or less similar to the original diaryl imidazole class [4,20,31,[72][73][74][75][76][77][78].…”

Section: Structural Features Of Small Molecule In-hibitorsmentioning

confidence: 99%

Pharmacophore Design of p38α MAP Kinase Inhibitors with Either 2,4,5-Trisubstituted or 1,2,4,5-Tetrasubstituted Imidazole Scaffold

Scior¹,

Domeyer²,

Cuanalo-Contreras³

et al. 2011

CMC

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Synthetic compounds with a tri- and tetra-substituted imidazole scaffold are known as selective inhibitors of the p38 mitogen-activated protein (MAP) kinase responsible for proinflammatory cytokine release. The scope is to review the literature describing their design, synthesis and activity studies. To date a great plethora of crystal structures of p38 in complex with small organic ligands have been published. Cocrystallized ligand information is of particular interest to our review study, i.e. ATP itself, the reference inhibitor SB203580 with its aryl-pyridinyl-imidazoles and related imidazole and pyrimidine-based derivatives. The selective inhibitors bind to the pocket of adenosine 5'-triphoshate (ATP) replacing the latter. The hydrophobic region II, however, is not occupied by the natural binder ATP, but accommodates the pyridine substituents preserving the 4-fluorophenyl ring occupation in pocket I as a prerequisite to gain higher binding selectivity and potency than the reference compound SB203580 (4-[5-(4-fluoro-phenyl)-2-(4-methanesulfinyl-phenyl)-3himidazol-4-yl]-pyridine). Experimental and computed work is reviewed which evidence that the 2 position of the pyrimidine ring is amenable to the introduction of a side chain and the replacement of pyridine in SB203580 by a pyrimidine ring improves both inhibitory activity and selectivity for p38 over other kinases. All ligands with a pyridyl C2 side chain occupy the hydrophobic pocket II and in some cases a double hydrogen bond is reported between methionine 109 and glycine 110 of the hinge region, following an observed backbone shift. The substituted pyridine ring binds stronger than the two other side chains on the imidazole scaffold.

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“…The respective substituted pyrimidylpyrazoles 13 a and 13 b [23,41] and isoxazoles 14 a and 14 b [42,43] were synthesized to develop the most appropriate scaffold. Biological testing revealed that the inhibitory potency of the sulfanylimidazoles is almost as good as that of the pyrazole scaffold and better than the isoxazole scaffold (Table 2).…”

Section: Biological Assaysmentioning

confidence: 99%

Synthesis and Biological Testing of N‐Aminoimidazole‐Based p38α MAP Kinase Inhibitors

et al. 2010

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The p38 mitogen-activated protein (MAP) kinase alpha plays a central role in the regulation of cellular responses such as differentiation, proliferation, apoptosis, and inflammation. Inhibition of p38 results in decreased synthesis of pro-inflammatory cytokines. To date, diverse p38alpha inhibitors are in phase II clinical trials for numerous cytokine-dependent diseases. 2-Sulfanylimidazole derivatives offer advantages over the prototype inhibitor SB 203580, including fewer cytochrome P450 interactions and better kinetic properties. The aim of this study was to develop novel 1,2,4,5-tetrasubstituted pyridinylimidazoles with acyl residues at the imidazole N1 position that can interact with the kinase's hydrophobic region II (HR II) or sugar pocket (SP) to improve both selectivity and activity. The substitution pattern was optimized by variation of the acyl moiety at the N1 position of the N-aminoimidazole core. Acylation of the amino function was used for optimization and led to potent p38alpha MAPK inhibitors.

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Substituted Isoxazoles as Potent Inhibitors of p38 MAP Kinase

Cited by 34 publications

References 43 publications

Evaluation of 3-(3-chloro-phenyl)-5-(4-pyridyl)-4,5-dihydroisoxazole as a Novel Anti-Inflammatory Drug Candidate

Evaluation of 3-(3-chloro-phenyl)-5-(4-pyridyl)-4,5-dihydroisoxazole as a Novel Anti-Inflammatory Drug Candidate

Pharmacophore Design of p38α MAP Kinase Inhibitors with Either 2,4,5-Trisubstituted or 1,2,4,5-Tetrasubstituted Imidazole Scaffold

Synthesis and Biological Testing of N‐Aminoimidazole‐Based p38α MAP Kinase Inhibitors

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Substituted Isoxazoles as Potent Inhibitors of p38 MAP Kinase

Cited by 34 publications

References 43 publications

Evaluation of 3-(3-chloro-phenyl)-5-(4-pyridyl)-4,5-dihydroisoxazole as a Novel Anti-Inflammatory Drug Candidate

Evaluation of 3-(3-chloro-phenyl)-5-(4-pyridyl)-4,5-dihydroisoxazole as a Novel Anti-Inflammatory Drug Candidate

Pharmacophore Design of p38&#945; MAP Kinase Inhibitors with Either 2,4,5-Trisubstituted or 1,2,4,5-Tetrasubstituted Imidazole Scaffold

Synthesis and Biological Testing of N‐Aminoimidazole‐Based p38α MAP Kinase Inhibitors

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Pharmacophore Design of p38α MAP Kinase Inhibitors with Either 2,4,5-Trisubstituted or 1,2,4,5-Tetrasubstituted Imidazole Scaffold