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

Abstract

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.

Comprehensive Review in Current Developments of Imidazole-Based Medicinal Chemistry

“…This might be explained by the fact that imidazole ring could interact with the amino group in the side chain of Lys53 by hydrogen bonds . Notably, imidazole derivative 230b gave much better inhibitory activity with an IC 50 value of 0.058 μM than compound 230a due to the additional acylated fragment that is able to interact with the kinase's hydrophobic region II or sugar pocket . Acylates 231a‐b obtained by acylation of the pyridine ring were also highly active against p38α MAPK with IC 50 values of 0.003 and 0.048 μM, respectively.…”

Environmental toxicants and male reproductive function

“…There are recent advances in the field using inhibitors against different MAPKs to treat various pathological conditions, mostly notably cancer, heart disease and pulmonary disease. [65][66][67][68] While many of these studies are in the stage of laboratory-based in vitro testing and studies, 65,67 several of these MAPK inhibitors or related kinase inhibitors have moved onto clinical studies. 66,68 Some of these clinical studies are now at the stages of data collection and analysis prior to the publication in peer-reviewed journals regarding their use to treat different illnesses ranging from late stage cancers to heart disease and inflammatory disorders (see www.ciscrp.org, www.nih.gov or www.cancer.gov for selected and additional references).…”

Insight into the Structural Determinants of Imidazole Scaffold-Based Derivatives as TNF-α Release Inhibitors by in Silico Explorations

“…Most of these small-molecular inhibitors of p38 MAP kinase are derived from the prototypical pyridin-4-ylimidazole SB203580, which definitely contributes to the identification and characterization of the p38 signaling pathway as a valid therapeutic target in inflammatory conditions [ 1 , 2 , 11 ]. Presently, based on the pyridin-4-ylimidazole SB203580, Laufer et al [ 2 , 10 , 18 , 19 ] have reported newer pyridinylimidazole inhibitors, which possess not only high p38α inhibitory activity, but also excellent inhibitory potency in suppression of the TNF-α release. In addition, these inhibitors have many other decisive advantages over prototype SB203580-like 2-arylimidazoles, e.g., higher selectivity, better kinetic and metabolic properties, and fewer interactions with metabolic enzymes like CYP450.…”

“…In the present work, 151 newly-synthesized imidazoles derivatives reported [ 2 , 10 , 18 , 19 ] as potent and selective TNF-α release inhibitors were employed as a data set to carry out a series of QSAR studies using a combination of CoMFA, CoMSIA, and pharmacophore modeling computational methods. The obtained CoMFA and CoMSIA studies not only illustrate the conformation or spatial orientation of those imidazole derivatives, but also provide useful indicators for the design of new drug candidates for inflammation diseases.…”