Divergent synthesis of kinase inhibitor derivatives, leading to discovery of selective Gck inhibitors

Takanori Matsumaru; Makoto Inai; Kana Ishigami; Toshiki Iwamatsu; Hiroshi Maita; Satoko Otsuguro; Takao Nomura; Akira Matsuda; Satoshi Ichikawa; Masahiro Sakaitani; Satoshi Shuto; Katsumi Maenaka; Toshiyuki Kan

doi:10.1016/j.bmcl.2017.03.055

Divergent synthesis of kinase inhibitor derivatives, leading to discovery of selective Gck inhibitors

Bioorg Med Chem Lett. 2017 May 15;27(10):2144-2147. doi: 10.1016/j.bmcl.2017.03.055. Epub 2017 Mar 23.

Affiliations

¹ Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
² School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
³ Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan. Electronic address: maenaka@pharm.hokudai.ac.jp.
⁴ School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. Electronic address: kant@u-shizuoka-ken.ac.jp.

PMID: 28385506
DOI: 10.1016/j.bmcl.2017.03.055

Abstract

We accomplished divergent synthesis of potent kinase inhibitor BAY 61-3606 (1) and 27 derivatives via conjugation of imidazo[1,2-c]pyrimidine and indole ring compounds with aromatic (including pyridine) derivatives by means of palladium-catalyzed cross-coupling reaction. Spleen tyrosine kinase (Syk) and germinal center kinase (Gck, MAP4K2) inhibition assays showed that some of the synthesized compounds were selective Gck inhibitors.

Keywords: BAY 61-3606; Gck; Imidazo[1,2-c]pyrimidine; Indole; Kinase inhibitor.

MeSH terms

Catalysis
Drug Evaluation, Preclinical
Germinal Center Kinases
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry*
Imidazoles / metabolism
Indoles / chemistry
Inhibitory Concentration 50
Niacinamide / analogs & derivatives
Niacinamide / chemistry
Niacinamide / metabolism
Palladium / chemistry
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / metabolism
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / metabolism
Structure-Activity Relationship
Syk Kinase / antagonists & inhibitors
Syk Kinase / metabolism

Substances

2-(7-(3,4-dimethoxyphenyl)imidazo(1,2-c)pyrimidin-5-ylamino)nicotinamide
Germinal Center Kinases
Imidazoles
Indoles
Protein Kinase Inhibitors
Pyrimidines
imidazo(1,2-c)pyrimidine
Niacinamide
Palladium
indole
Syk Kinase
Protein Serine-Threonine Kinases