Novel Substituted Pyridinyl Imidazoles as Potent Anticytokine Agents with Low Activity against Hepatic Cytochrome P450 Enzymes

Abstract

A series of polysubstituted pyridin-4-yl imidazole inhibitors of p38 MAP (mitogen-activated protein) kinase was prepared as small molecular anticytokine agents and drug candidates for the treatment of chronic inflammatory diseases. The contribution of substituents at the pyridinyl and imidazole moiety to selective inhibition of p38 without concomitant cytochrome P450 interaction was evaluated. Placement of a 1-phenylethyl (7e, p38: IC(50) 0.38 microM) or acetyl substituent at the exocyclic nitrogen of several 2-aminopyridine imidazoles led to the identification of potent p38 inhibitors which exceeded the starting lead ML 3375 (p38: IC(50) 0.63 microM) in potency. A preliminary modeling study related the enhanced bioactivity of 7e to a novel interaction between its 1-phenylethylamino side chain and a hydrophobic pocket close to the linker region of p38. The most active p38 inhibitors in this series maintained their efficacy in functional PBMC (peripheral blood mononuclear cells) and whole blood assays. Moreover, cytochrome P450 interaction, which has been linked to the liver toxicity observed for model p38 inhibitors, was very efficiently reduced through introduction of a tetramethylpiperidine substituent at the 1 position of the imidazole nucleus. Combination of both structural features provided 14c (p38: 0.34 microM, inhibition of CYP1A2 0%, 2C9 2.6%, 2C19 7.6% at 10 microM), which was selected for further development.

Quantitative Proteomic and Transcriptional Analysis of the Response to the p38 Mitogen-activated Protein Kinase Inhibitor SB203580 in Transformed Follicular Lymphoma Cells

“…Similarly, SB203580 has been shown to affect the activity of the hepatic cytochrome P450 enzymes (119). This activity is explained by the fact that pyridine and imidazole components of the SB203580 compound are ligands for the heme iron of cytochrome P450 (120). Interestingly, our studies revealed 5.2-fold induction of an isoform of cytochrome P450, supporting the previously described interaction between SB203580 and cytochrome P450.…”

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

“…Several modifications of the diarylimidazoles resulted in an improvement of p38 MAP kinase selectivity and a reduction of P450 inhibition (Laufer et al, 2003). However, keeping in mind that minor modifications of the chemical structure could have a dramatic impact on the protein kinase selectivity, metabolism studies with protein kinase inhibitors are of great importance.…”

“…ML3403 ({4-[5-(4-fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]-pyridin-2-yl}-(1-phenylethyl)-amine) (Fig. 1) belongs to the second generation of diarylimidazole-type p38 MAP kinase inhibitors (Laufer et al, 2003). The potency toward p38␣ is approximately 2-fold compared with SB203580, and in BALB/c mice, the lipopolysaccharide/D-galactosamine-induced release of TNF-␣ was completely inhibited when doses of 30 and 100 mg/kg body weight ML3403 were orally administered 1 h before the lipopolysaccharide/D-galactosamine challenge.…”

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

“…Only alkyl residues have been probed at the imidazole N1 position. [25,26] However, results of docking pyridinylimidazoles into the ATP binding site of p38a MAPK (template PDB ID: 1A9U) demonstrated that there should be sufficient space in HR II for larger acyl residues.…”

“…[25,26,28] Attempts to prepare suitably substituted triazinanes failed. Therefore, a novel synthesis was developed to construct N-[4-(4-fluorophenyl)-2-methylthio-5-(pyridin-4-yl)-1H-imidazol-1-yl]amide compounds.…”