Discovery of imidazo[1,2-b]pyridazines as IKKβ inhibitors. Part 3: exploration of effective compounds in arthritis models.

Abstract

We have discovered imidazo[1,2-b]pyridazine derivatives that show suppressive activity of inflammation in arthritis models. We optimized the substructures of imidazo[1,2-b]pyridazine derivatives to combine potent IKKβ inhibitory activity, TNFα inhibitory activity in vivo and excellent pharmacokinetics. The compound we have acquired, which had both potent activities and good pharmacokinetic profiles based on improved physicochemical properties, demonstrated efficacy on collagen-induced arthritis models in mice and rats.

• Authors: Hiroki Shimizu, Tomonori Yamasaki, Yoshiyuki Yoneda, Fumihito Muro, Tomoaki Hamada, Takanori Yasukochi, Shinji Tanaka, Tadashi Toki, Mika Yokoyama, Kaoru Morishita, Shin Iimura
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 21 Issue 15 Pg. 4550-5 (Aug 01 2011) ISSN: 1464-3405 [Electronic] England
• PMID: 21705219 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Imidazoles
• Protein Kinase Inhibitors
• Pyridazines
• Tumor Necrosis Factor-alpha
• imidazole
• I-kappa B Kinase

Topics

• Administration, Oral
• Animals
• Arthritis, Experimental (drug therapy)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• I-kappa B Kinase (antagonists & inhibitors, metabolism)
• Imidazoles (chemistry)
• Mice
• Protein Kinase Inhibitors (chemistry, pharmacokinetics, therapeutic use)
• Pyridazines (chemistry, pharmacokinetics, therapeutic use)
• Rats
• Tumor Necrosis Factor-alpha (metabolism)