Discovery of potent and orally active tricyclic-based FBPase inhibitors

被引：6

作者：

Tsukada, Tomoharu ^{[1
]}

Kanno, Osamu ^{[1
]}

Yamane, Takahiro ^{[1
]}

Tanaka, Jun ^{[2
]}

Yoshida, Taishi ^{[2
]}

Okuno, Akira ^{[2
]}

Shiiki, Takeshi ^{[3
]}

Takahashi, Mizuki ^{[4
]}

Nishi, Takahide ^{[1
]}

机构：

[1] Daiichi Sankyo Co Ltd, Med Chem Res Labs 1, Shinagawa Ku, Tokyo 1408710, Japan

[2] Daiichi Sankyo Co Ltd, Biol Res Labs 2, Shinagawa Ku, Tokyo 1408710, Japan

[3] Daiichi Sankyo Co Ltd, Drug Metab & Pharmacokinet Res Labs, Shinagawa Ku, Tokyo 1408710, Japan

[4] Daiichi Sankyo Co Ltd, Exploratory Res Labs 1, Edogawa Ku, Tokyo 1348630, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2010年 / 18卷 / 14期

关键词：

Fructose-1,6-bisphosphatase; FBPase inhibitors; Prodrug; MOLECULAR-SURFACE PROPERTIES; FRUCTOSE 1,6-BISPHOSPHATASE; BENZOXAZOLE BENZENESULFONAMIDES; ALLOSTERIC INHIBITORS; GLUCOSE-PRODUCTION; DIABETES-MELLITUS; AMP SITE; FRUCTOSE-1,6-BISPHOSPHATASE; GLUCONEOGENESIS; PERMEABILITY;

D O I：

10.1016/j.bmc.2010.05.041

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

With the aim of exploring the effect of tricyclic-based FBPase inhibitors in cells and in vivo, a series of prodrugs of tricyclic phosphonates was designed and synthesized. Introducing prodrug moieties into tricyclic-based phosphonates led to the discovery of prodrug 15c, which strongly inhibited glucose production in monkey hepatocytes. Furthermore, prodrug 15c lowered blood glucose levels in fasted cynomolgus monkeys. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：5346 / 5351

页数：6

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