Structure‐Based Design, Synthesis, and Biological Evaluation of Imidazo[4,5‐b]Pyridin‐2‐one‐Based p38 MAP Kinase Inhibitors: Part 2

  title={Structure‐Based Design, Synthesis, and Biological Evaluation of Imidazo[4,5‐b]Pyridin‐2‐one‐Based p38 MAP Kinase Inhibitors: Part 2},
  author={Akira Kaieda and Masashi Takahashi and Hiromitsu Fukuda and Rei Okamoto and Shinji Morimoto and Masayuki Gotoh and Takahiro Miyazaki and Yuri Hori and Satoko Unno and Tomohiro Kawamoto and Toshimasa Tanaka and Sachiko Itono and Terufumi Takagi and Hiroshi Sugimoto and Kengo Okada and Weston Lane and Biching Sang and Kumar Singh Saikatendu and Shin-ichiro Matsunaga and Seiji Miwatashi},
We identified novel potent inhibitors of p38 mitogen‐activated protein (MAP) kinase using a structure‐based design strategy, beginning with lead compound, 3‐(butan‐2‐yl)‐6‐(2,4‐difluoroanilino)‐1,3‐dihydro‐2H‐imidazo[4,5‐b]pyridin‐2‐one (1). To enhance the inhibitory activity of 1 against production of tumor necrosis factor‐α (TNF‐α) in human whole blood (hWB) cell assays, we designed and synthesized hybrid compounds in which the imidazo[4,5‐b]pyridin‐2‐one core was successfully linked with the… 
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Structure‐Based Design, Synthesis, and Biological Evaluation of Imidazo[4,5‐b]pyridin‐2‐one‐Based p38 MAP Kinase Inhibitors: Part 1

The discovery of potent and orally bioavailable imidazo[4,5‐b]pyridin‐2‐one‐based p38 MAP kinase inhibitors that suppressed cytokine production in a human whole blood cell‐based assay is described.

Discovery of N-{4-[5-(4-Fluorophenyl)-3-methyl-2-methylsulfanyl-3H-imidazol-4-yl]-pyridin-2-yl}-acetamide (CBS-3595), a Dual p38α MAPK/PDE-4 Inhibitor with Activity against TNFα-Related Diseases.

It was demonstrated that dual inhibition of p38α MAPK and PDE4 is able to synergistically attenuate the excessive anti-inflammatory response.

Discovery of 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases.

Inhibitor 7k is slightly less active than 1a in the p38α enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model.

Novel inhibitor of p38 MAP kinase as an anti-TNF-alpha drug: discovery of N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (TAK-715) as a potent and orally active anti-rheumatoid arthritis agent.

A novel series of 4-phenyl-5-pyridyl-1,3-thiazoles synthesized and evaluated their inhibition of p38 MAP kinase, lipopolysaccharide (LPS)-stimulated release of tumor necrosis factor-alpha from human monocytic THP-1 cells in vitro, and LPS-induced TNF-alpha production in vivo in mice showed potent inhibitory activity.

Targeting the hinge glycine flip and the activation loop: novel approach to potent p38α inhibitors.

Dibenzepinones, dibenzoxepines, and benzosuberones are reported as p38α MAP kinase inhibitors, and interactions with the DFG-motif in the in-conformation could be observed by protein X-ray crystallography.

p38alpha mitogen-activated protein kinase inhibitors: optimization of a series of biphenylamides to give a molecule suitable for clinical progression.

This paper describes how a series of novel p38alpha/beta inhibitors are optimized using crystal structures of their inhibitors bound to p38 alpha, classical medicinal chemistry, and modeling of virtual libraries to derive a molecule suitable for progression into clinical development.

Biphenyl amide p38 kinase inhibitors 3: Improvement of cellular and in vivo activity.

Pathway to the clinic: inhibition of P38 MAP kinase. A review of ten chemotypes selected for development.

These results, in addition to proof of concept studies in rheumatoid patients, have established p38 inhibition as an avenue for the future management of pro-inflammatory cytokine based diseases.