title: Rational design and synthesis of 4-substituted 2-pyridin-2-ylamides with inhibitory effects on SH2 domain-containing inositol 5'-phosphatase 2 (SHIP2).
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.
authors: Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
authors: Yoshinori
authors: Y
authors: Ichihara
authors: Ryohei
authors: R
authors: Fujimura
authors: Hiroshi
authors: H
authors: Tsuneki
authors: Tsutomu
authors: T
authors: Wada
authors: Kentaro
authors: K
authors: Okamoto
authors: Hiroaki
authors: H
authors: Gouda
authors: Shuichi
authors: S
authors: Hirono
authors: Kenji
authors: K
authors: Sugimoto
authors: Yuji
authors: Y
authors: Matsuya
authors: Toshiyasu
authors: T
authors: Sasaoka
authors: Naoki
authors: N
authors: Toyooka
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D044482:Benzeneacetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D015394:Molecular Structure; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D018909:src Homology Domains / Q000187:drug effects*
chemical_list: D044482:Benzeneacetamides; D004791:Enzyme Inhibitors; C583787:N-(4-(4-chlorobenzyloxy)pyridin-2-yl)-2-(2,6-difluorophenyl)acetamide; D011725:Pyridines; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases