Discovery of imidazo[1,2-b]pyridazines as IKKβ inhibitors. Part 2: improvement of potency in vitro and in vivo

Hiroki Shimizu; Isao Yasumatsu; Tomoaki Hamada; Yoshiyuki Yoneda; Tomonori Yamasaki; Shinji Tanaka; Tadashi Toki; Mika Yokoyama; Kaoru Morishita; Shin Iimura

doi:10.1016/j.bmcl.2010.12.078

Discovery of imidazo[1,2-b]pyridazines as IKKβ inhibitors. Part 2: improvement of potency in vitro and in vivo

Bioorg Med Chem Lett. 2011 Feb 1;21(3):904-8. doi: 10.1016/j.bmcl.2010.12.078. Epub 2010 Dec 21.

Authors

Hiroki Shimizu¹, Isao Yasumatsu, Tomoaki Hamada, Yoshiyuki Yoneda, Tomonori Yamasaki, Shinji Tanaka, Tadashi Toki, Mika Yokoyama, Kaoru Morishita, Shin Iimura

Affiliation

¹ R&D Division, Daiichi Sankyo Co., Ltd, Edogawa-ku, Tokyo, Japan. [email protected]

PMID: 21232950
DOI: 10.1016/j.bmcl.2010.12.078

Abstract

We have increased the potency of imidazo[1,2-b]pyridazine derivatives as IKKβ inhibitors with two strategies. One is to enhance the activity in cell-based assay by adjusting the polarity of molecules to improve permeability. Another is to increase the affinity for IKKβ by the introduction of additional substituents based on the hypothesis derived from an interaction model study. These improved compounds showed inhibitory activity of TNFα production in mice.

MeSH terms

Animals
Binding Sites
Computer Simulation
Drug Evaluation, Preclinical
I-kappa B Kinase / antagonists & inhibitors*
I-kappa B Kinase / metabolism
Male
Mice
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology
Pyridazines / chemical synthesis
Pyridazines / chemistry*
Pyridazines / pharmacology
Structure-Activity Relationship
Tumor Necrosis Factor-alpha / metabolism

Substances

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