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.
Yoshinori Ichihara  1 ,  Ryohei Fujimura ,  Hiroshi Tsuneki ,  Tsutomu Wada ,  Kentaro Okamoto ,  Hiroaki Gouda ,  Shuichi Hirono ,  Kenji Sugimoto ,  Yuji Matsuya ,  Toshiyasu Sasaoka ,  Naoki Toyooka
Affiliations
  • 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.

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