Synthesis of 5-chloro-N-aryl-1H-indole-2-carboxamide derivatives as inhibitors of human liver glycogen phosphorylase a

被引：33

作者：

Onda, Kenichi ^{[1
]}

Suzuki, Takayuki ^{[1
]}

Shiraki, Ryota ^{[1
]}

Yonetoku, Yasuhiro ^{[1
]}

Negoro, Kenji ^{[1
]}

Momose, Kazuhiro ^{[1
]}

Katayama, Naoko ^{[1
]}

Orita, Masaya ^{[1
]}

Yamaguchi, Tomohiko ^{[1
]}

Ohta, Mitsuaki ^{[1
]}

Tsukamoto, Shin-ichi ^{[1
]}

机构：

[1] Astellas Pharma Inc, Drug Discovery Res, Tsukuba, Ibaraki 3002698, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2008年 / 16卷 / 10期

关键词：

glycogen phosphorylase; hepatic glucose output; diabetes; crystallographic determination;

D O I：

10.1016/j.bmc.2008.04.010

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 [生物化学与分子生物学]; 081704 [应用化学];

摘要：

A series of 5-chloro-N-aryl-1H-indole-2-carboxamide derivatives were prepared and evaluated as inhibitors of human liver glycogen phosphorylase a (hLGPa). One compound, 5-chloro-N-[4-(1,2-dihydroxyethyl) phenyl]-1H-indole-2-carboxamide (2f), inhibited hLGPa with an IC(50) of 0.90 mu M. The pyridine analogue of 2f showed inhibitory activity of glucagon-induced glucose output in cultured primary hepatocytes with an IC(50) of 0.62 mu M and oral hypoglycemic activity in diabetic db/db mice. Crystallographic determination of the complex of 2f with hLGPa showed binding of the inhibitor in a solvent cavity at the dimer interface, with the two hydroxyl groups making favorable electrostatic interactions with hLGPa. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：5452 / 5464

页数：13

共 34 条

[1]

WITTIG REACTIONS INITIATED BY DEALKYLATIVE DECARBOXYLATION [J].

BELLETIRE, JL ;

WALLEY, DR ;

BAST, MJ .

SYNTHETIC COMMUNICATIONS, 1982, 12 (06) :469-475

[2]

EFFECTS OF PARA-SUBSTITUENTS ON THE MECHANISMS OF SOLVOLYSIS OF STYRENE OXIDES [J].

BLUMENSTEIN, JJ ;

UKACHUKWU, VC ;

MOHAN, RS ;

WHALEN, DL .

JOURNAL OF ORGANIC CHEMISTRY, 1993, 58 (04) :924-932

[3]

Crystallography & NMR system:: A new software suite for macromolecular structure determination [J].

Brunger, AT ;

Adams, PD ;

Clore, GM ;

DeLano, WL ;

Gros, P ;

Grosse-Kunstleve, RW ;

Jiang, JS ;

Kuszewski, J ;

Nilges, M ;

Pannu, NS ;

Read, RJ ;

Rice, LM ;

Simonson, T ;

Warren, GL .

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1998, 54 :905-921

[4]

CLARK AK, 2006, CHEM COMPUT GROUP J

[5]

ROLE OF LIVER IN PATHOPHYSIOLOGY OF NIDDM [J].

CONSOLI, A .

DIABETES CARE, 1992, 15 (03) :430-441

[6]

Pharmacologic therapy for type 2 diabetes mellitus [J].

DeFronzo, RA .

ANNALS OF INTERNAL MEDICINE, 1999, 131 (04) :281-303

[7]

PATHOGENESIS OF NIDDM - A BALANCED OVERVIEW [J].

DEFRONZO, RA ;

BONADONNA, RC ;

FERRANNINI, E .

DIABETES CARE, 1992, 15 (03) :318-368

[8]

THE TRIUMVIRATE - BETA-CELL, MUSCLE, LIVER - A COLLUSION RESPONSIBLE FOR NIDDM [J].

DEFRONZO, RA .

DIABETES, 1988, 37 (06) :667-687

[9]

Kinetic and functional characterization of 1,4-dideoxy-1,4-imino-D-arabinitol: A potent inhibitor of glycogen phosphorylase with anti-hyperglyceamic effect in ob/ob mice [J].

Fosgerau, K ;

Westergaard, N ;

Quistorff, B ;

Grunnet, N ;

Kristiansen, M ;

Lundgren, K .

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 2000, 380 (02) :274-284

[10]

GERICH JE, 1992, HORM METAB RES, V26, P18

← 1 2 3 4 →