Rational design and synthesis of 4-substituted 2-pyridin-2-ylamides with inhibitory effects on SH2 domain-containing inositol 5'-phosphatase 2 (SHIP2)

Yoshinori Ichihara; Ryohei Fujimura; Hiroshi Tsuneki; Tsutomu Wada; Kentaro Okamoto; Hiroaki Gouda; Shuichi Hirono; Kenji Sugimoto; Yuji Matsuya; Toshiyasu Sasaoka; Naoki Toyooka

doi:10.1016/j.ejmech.2013.01.014

Rational design and synthesis of 4-substituted 2-pyridin-2-ylamides with inhibitory effects on SH2 domain-containing inositol 5'-phosphatase 2 (SHIP2)

Eur J Med Chem. 2013 Apr:62:649-60. doi: 10.1016/j.ejmech.2013.01.014. Epub 2013 Jan 28.

Authors

Yoshinori Ichihara¹, Ryohei Fujimura, Hiroshi Tsuneki, Tsutomu Wada, Kentaro Okamoto, Hiroaki Gouda, Shuichi Hirono, Kenji Sugimoto, Yuji Matsuya, Toshiyasu Sasaoka, Naoki Toyooka

Affiliation

¹ Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.

PMID: 23434638
DOI: 10.1016/j.ejmech.2013.01.014

Abstract

Novel 4-substituted 2-pyridin-2-ylamides were developed using in-silico ligand-based drug design (LBDD) in an attempt to identify inhibitors of SH2-containing 5'-inositol phosphatase 2 (SHIP2), which is implicated in insulin-resistant type 2 diabetes. Among the compounds synthesized, N-[4-(4-chlorobenzyloxy)pyridin-2-yl]-2-(2,6-difluorophenyl)- acetamide (CPDA, 4a) was identified as a potent SHIP2 inhibitor. CPDA was found to enhance in vitro insulin signaling through the Akt pathway more efficiently than the previously reported SHIP2 inhibitor AS1949490, and ameliorated abnormal glucose metabolism in diabetic (db/db) mice.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3T3-L1 Cells
Animals
Benzeneacetamides / chemical synthesis
Benzeneacetamides / chemistry
Benzeneacetamides / pharmacology*
Cells, Cultured
Dose-Response Relationship, Drug
Drug Design*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Obese
Molecular Structure
Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
Phosphoric Monoester Hydrolases / antagonists & inhibitors*
Phosphoric Monoester Hydrolases / metabolism
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Structure-Activity Relationship
src Homology Domains / drug effects*

Substances

Benzeneacetamides
Enzyme Inhibitors
N-(4-(4-chlorobenzyloxy)pyridin-2-yl)-2-(2,6-difluorophenyl)acetamide
Pyridines
Phosphoric Monoester Hydrolases
INPPL1 protein, human
Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases