Synthesis and Mechanism of Hypoglycemic Activity of Benzothiazole Derivatives

被引：88

作者：

Meltzer-Mats, Ella ^{[1
]}

Babai-Shani, Gali ^{[2
]}

Pasternak, Lily ^{[2
]}

Uritsky, Neta ^{[1
]}

Getter, Tamar ^{[1
]}

Viskind, Olga ^{[1
,2
]}

Eckel, Juergen ^{[3
]}

Cerasi, Erol ^{[4
]}

Senderowitz, Hanoch ^{[1
]}

Sasson, Shlomo ^{[2
]}

Gruzman, Arie ^{[1
]}

机构：

[1] Bar Ilan Univ, Fac Exact Sci, Dept Chem, Div Med Chem, IL-5290002 Ramat Gan, Israel

[2] Hebrew Univ Jerusalem, Sch Pharm, Dept Pharmacol, Inst Drug Res,Fac Med, IL-91120 Jerusalem, Israel

[3] German Diabet Ctr, Paul Langerhans Grp, D-40225 Dusseldorf, Germany

[4] Hadassah Hebrew Univ, Dept Med, Endocrinol & Metab Serv, Med Ctr, IL-91120 Jerusalem, Israel

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 13期

基金：

以色列科学基金会;

关键词：

ACTIVATED PROTEIN-KINASE; SKELETAL-MUSCLE; INSULIN-RESISTANCE; TRANSPORT SYSTEM; GLUCOSE-UPTAKE; CELLS; AMPK;

D O I：

10.1021/jm4001488

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Adenosine 5'-monophosphate activated protein kinase (AMPK) has emerged as a major potential target for novel antidiabetic drugs. We studied the structure of 2-chloro-5-((Z)-((E)-5-((5-(4,5-dimethyl-2-nitrophenyl)furan-2-yl)methylene)-4-oxothiazolidin-2-ylidene)amino)benzoic acid (PT-1), which attenuates the autoinhibition of the enzyme AMPK, for the design and synthesis of different benzothiazoles with potential antidiabetic activity. We synthesized several structurally related benzothiazole derivatives that increased the rate of glucose uptake in L6 myotubes in an AMPK-dependent manner. One compound, 2-(benzo[d]thiazol-2-ylmethylthio)-6-ethoxybenzo[d]thiazole (34), augmented the rate of glucose uptake up to 2.5-fold compared with vehicle-treated cells and up to 1.1-fold compared to PT-1. Concomitantly, it elevated the abundance of GLUT4 in the plasma membrane of the myotubes and activated AMPK. Subcutaneous administration of 34 to hyperglycemic Kuo Kondo rats carrying the Ay-yellow obese gene (KKAy) mice lowered blood glucose levels toward the normoglycemic range. In accord with its activity, compound 34 showed a high fit value to a pharmacophore model derived from the PT-1.

引用

页码：5335 / 5350

页数：16