title: Discovery of a novel protein tyrosine phosphatase-1B inhibitor, KR61639: potential development as an antihyperglycemic agent.
abstract: Protein tyrosine phosphatase-1B (PTP-1B), a negative regulator of insulin signaling, may be an attractive therapeutic target for type 2 diabetes mellitus. High throughput screening (HTS) for PTP-1B inhibitors using compounds from the Korea Chemical Bank identified several hits (active compounds). Among them, a hit with 1,2-naphthoquinone scaffold was chosen for lead development. KR61639, [4-[1-(1H-indol-3-yl)-3,4-dioxo-3,4-dihydro-naphthalen-2-ylmethyl]-phenoxy]-acetic acid tert-butyl ester, inhibited human recombinant PTP-1B with an IC(50) value of 0.65 microM in a noncompetitive manner. KR61639 showed modest selectivity over several phosphatases and increased insulin-stimulated glycogen synthesis in HepG2 cells and stimulated 2-deoxyglucose uptake in 3T3/L1 adipocytes. In addition, in vivo study using ob/ob mouse demonstrated that KR61639 exerted a hypoglycemic action when given orally. Thus, KR61639 may be a good starting point for lead optimization in developing a novel antidiabetic agent.
authors.affiliation: Medicinal Science Division, Pharmaceutical Screening Center, Korea Research Institute of Chemical Technology, Jang-Dong 100, Yusung-Gu, TaeJon 305-343, South Korea. hgcheon@krict.re.kr
authors.forename: Hyae Gyeong
authors.initials: HG
authors.lastname: Cheon
authors.forename: Sun-Mee
authors.initials: SM
authors.lastname: Kim
authors.forename: Sung-Don
authors.initials: SD
authors.lastname: Yang
authors.forename: Jae Du
authors.initials: JD
authors.lastname: Ha
authors.forename: Joong-Kwon
authors.initials: JK
authors.lastname: Choi
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D009281:Naphthalenes / Q000737:chemistry* / Q000494:pharmacology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007211:Indoles; D007328:Insulin; D007527:Isoenzymes; C491551:KR61639; D009281:Naphthalenes; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse