期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 485, 期 1-3, 页码 333-339出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2003.11.070
关键词
PTP-1B (protein tyrosine phosphatase-1B); 1,2-naphthoquinone; deoxyglucose uptake; glycogen incorporation; ob/ob mouse
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 IC50 value of 0.65 muM 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. (C) 2004 Elsevier B.V. All rights reserved.
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