Synthesis and structure-activity relationships of novel IKK-beta inhibitors. Part 2: Improvement of in vitro activity

Toshiki Murata; Mitsuyuki Shimada; Hiroshi Kadono; Sachiko Sakakibara; Takashi Yoshino; Tsutomu Masuda; Makoto Shimazaki; Takuya Shintani; Kinji Fuchikami; Kevin B Bacon; Karl B Ziegelbauer; Timothy B Lowinger

doi:10.1016/j.bmcl.2004.05.040

Synthesis and structure-activity relationships of novel IKK-beta inhibitors. Part 2: Improvement of in vitro activity

Bioorg Med Chem Lett. 2004 Aug 2;14(15):4013-7. doi: 10.1016/j.bmcl.2004.05.040.

Authors

Toshiki Murata¹, Mitsuyuki Shimada, Hiroshi Kadono, Sachiko Sakakibara, Takashi Yoshino, Tsutomu Masuda, Makoto Shimazaki, Takuya Shintani, Kinji Fuchikami, Kevin B Bacon, Karl B Ziegelbauer, Timothy B Lowinger

Affiliation

¹ Department of Chemistry, Research Center Kyoto, Bayer Yakuhin Ltd., Kizu, Soraku, Kyoto 619-0216, Japan. [email protected]

PMID: 15225717
DOI: 10.1016/j.bmcl.2004.05.040

Abstract

A series of 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl)pyridine derivatives was synthesized and evaluated as IkappaB kinase beta (IKK-beta) inhibitors. Substitution of an aminoalkyl group for the aromatic group at the 4-position on the core pyridine ring resulted in a marked increase in both kinase enzyme and cellular potencies, and provided potent IKK-beta inhibitors with IC(50) values of below 100 nM.

MeSH terms

Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
I-kappa B Kinase
Kinetics
Models, Molecular
Molecular Conformation
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Recombinant Proteins / antagonists & inhibitors
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Recombinant Proteins
Protein Serine-Threonine Kinases
CHUK protein, human
I-kappa B Kinase
IKBKB protein, human
IKBKE protein, human