Pharmacokinetics of ML3403 ({4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3<i>H</i>-imidazol-4-yl]-pyridin-2-yl}-(1-phenylethyl)-amine), a 4-Pyridinylimidazole-Type p38 Mitogen-Activated Protein Kinase Inhibitor

Kammerer, Bernd; Scheible, Holger; Albrecht, Wolfgang; Gleiter, Christoph H.; Laufer, Stefan

doi:10.1124/dmd.106.013409

Cited by 21 publications

(17 citation statements)

References 21 publications

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“…8,35 Here, 2-sulfanylimidazoles and their active in vivo metabolic transformation products (sulfoxides, sulfones) demonstrated decisive advantages over prototype SB203580-like 2-arylimidazoles, e.g., fewer interactions with metabolic enzymes like CYP450 and better kinetic and metabolic properties. [36][37][38][39] The 2-alkylsulfanyl-5-(pyridin-4-yl)imidazoles III and IV ( Figure 5) have been recently recognized as strong inhibitors of both the isolated p38 MAP kinase and cytokine release in PBMCs as well as in human whole blood, with IC 50 values in the low micromolar range, comparable to those of the potent model compound SB203580. 36 Furthermore, CYP450-dependent toxic side effects were decisively reduced, thus showing a general advantage of 2-thioimidazoles compared to prototypical SB-like 2-aryl-subtituted derivatives.…”

Section: Introductionmentioning

confidence: 98%

Design, Synthesis, and Biological Evaluation of Novel Tri- and Tetrasubstituted Imidazoles as Highly Potent and Specific ATP-Mimetic Inhibitors of p38 MAP Kinase: Focus on Optimized Interactions with the Enzyme’s Surface-Exposed Front Region

et al. 2008

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The synthesis, biological testing, and SAR of novel 2,4,5- and 1,2,4,5-substituted 2-thioimidazoles are described. Amino, oxy, or thioxy substituents at the 2-position of the pyridinyl moiety were evaluated for their contributions to inhibitor potency and selectivity against p38 mitogen activated protein kinase (p38 MAPK) as well as for the ability to minimize cytochrome P450 (CYP450) inhibition. Incorporation of polar substituted (cyclo)aliphatic amino substituents (e.g., tetrahydropyranylamino), which positively interacted with the surface-exposed front region (hydrophobic region II) of the enzyme led to the identification of extremely potent p38 MAPK inhibitors with p38 IC 50 values in the low nanomolar range. Approximately 90 pyridinylimidazole-based compounds with a range of potencies against p38alpha MAP kinase were further investigated for their ability to inhibit the release of tumor necrosis factor-alpha (TNFalpha) and/or interleukin-1beta (IL-1beta) from human whole blood. Some of the most promising drug candidates underwent selectivity profiling against a panel of 17 different kinases besides p38alpha and/or were tested for their interaction potential toward a number of metabolically relevant CYP450 isozymes.

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Section: Introductionmentioning

confidence: 98%

Design, Synthesis, and Biological Evaluation of Novel Tri- and Tetrasubstituted Imidazoles as Highly Potent and Specific ATP-Mimetic Inhibitors of p38 MAP Kinase: Focus on Optimized Interactions with the Enzyme’s Surface-Exposed Front Region

et al. 2008

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“…Inhibition of the protein kinases represents an attractive strategy for therapeutic intervention. In particular, the p38 MAPK inhibitors have been used in the in vitro and in vivo systems as well as in the clinical trials [6,7]. This is further supported by the fact that SB202190 and ML3403, inhibitors of p38 MAPK, led to dephosphorylation of EmMPK2 in Echinococcus multilocularis and effectively killed parasite vesicles [8].…”

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confidence: 99%

In Vitro Effects of SB202190 on Echinococcus granulosus

Liu

Zhang

et al. 2013

Korean J Parasitol

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Spillage of cyst contents during surgical operation is the major cause of recurrence after hydatid cyst surgery. Instillation of a scolicidal agent into a hepatic hydatid cyst is the most commonly employed measure to prevent this complication. SB202190 is a pyridinyl imidazole derivative and is known to be a specific inhibitor of p38 MAPK. In the present study, the scolicidal effect of SB202190 was investigated. Freshly isolated Echinococcus granulosus protoscolices were subjected to SB202190 treatment (10, 20, 40, and 80 µM), and the effects on parasite viability were monitored by trypan blue staining. Corresponding effects were visualized by scanning and transmission electron microscopy. Dose-dependent protoscolex death within a few days of SB202190 treatment was observed. Although the in vitro scolicidal effect of SB202190 was satisfactory, the in vivo efficacy of this drug and also possible side effects remain to be further investigated.

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“…Moieties such as the phenylethylamine group may be easily dealkylated in HLM. [31,32] On the other hand, 2-acylaminopyridinyl compounds such as TAK-715 show enhanced metabolic stability. [33] However, few structure-activity relationships on acyl derivatives within the imidazole series are known, because only the acetyl moiety has been probed so far.…”

Section: Scaffold Designmentioning

confidence: 99%

2‐Acylaminopyridin‐4‐ylimidazoles as p38 MAP Kinase Inhibitors: Design, Synthesis, and Biological and Metabolic Evaluations

Ziegler

Hauser

Unger³

et al. 2009

ChemMedChem

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Targeting cytokines has become an important focus in the treatment of many inflammatory disorders. p38 MAP kinase (MAPK) is the key enzyme in regulating the biosynthesis and release of pro-inflammatory cytokines such as IL-1beta and TNFalpha. Inhibition of p38 MAPK results in decreased expression of these cytokines. Tri- and tetrasubstituted pyridinylimidazoles are potent inhibitors of p38 MAPK. Substitution on the pyridinyl moiety allows the design of inhibitors that show increased selectivity and activity by targeting the enzyme's hydrophobic region II. The objective of this study was to synthesize novel 1,2,4,5-tetrasubstituted imidazole derivates and to characterize them not only for their ability to inhibit p38 MAPK and modulate cytokine release in human whole blood, but also to evaluate their metabolic stability. Biological data and metabolic studies demonstrate that the introduction of a 2-acylamino function at C2 of the pyridine results in highly efficient and metabolically stable inhibitors relative to C2-alkylamino derivatives. A series of novel candidates was investigated for metabolic stability in human liver microsomes and in human whole blood. Additionally, metabolic S-oxidation was investigated, and possible metabolites were synthesized.

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Pharmacokinetics of ML3403 ({4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]-pyridin-2-yl}-(1-phenylethyl)-amine), a 4-Pyridinylimidazole-Type p38 Mitogen-Activated Protein Kinase Inhibitor

Cited by 21 publications

References 21 publications

Design, Synthesis, and Biological Evaluation of Novel Tri- and Tetrasubstituted Imidazoles as Highly Potent and Specific ATP-Mimetic Inhibitors of p38 MAP Kinase: Focus on Optimized Interactions with the Enzyme’s Surface-Exposed Front Region

Design, Synthesis, and Biological Evaluation of Novel Tri- and Tetrasubstituted Imidazoles as Highly Potent and Specific ATP-Mimetic Inhibitors of p38 MAP Kinase: Focus on Optimized Interactions with the Enzyme’s Surface-Exposed Front Region

In Vitro Effects of SB202190 on Echinococcus granulosus

2‐Acylaminopyridin‐4‐ylimidazoles as p38 MAP Kinase Inhibitors: Design, Synthesis, and Biological and Metabolic Evaluations

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