Synthesis, Crystallization, and Biological Evaluation of an Orally Active Prodrug of Gemcitabine

被引：92

作者：

Bender, David M. ^{[1
]}

Bao, Jingqi ^{[1
]}

Dantzig, Anne H. ^{[1
]}

Diseroad, William D. ^{[1
]}

Law, Kevin L. ^{[1
]}

Magnus, Nicholas A. ^{[1
]}

Peterson, Jeffrey A. ^{[1
]}

Perkins, Everett J. ^{[1
]}

Pu, Yangwei J. ^{[1
]}

Reutzel-Edens, Susan M. ^{[1
]}

Remick, David M. ^{[1
]}

Starling, James J. ^{[1
]}

Stephenson, Gregory A. ^{[1
]}

Vaid, Radhe K. ^{[1
]}

Zhang, Deyi ^{[1
]}

McCarthy, James R. ^{[1
]}

机构：

[1] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 22期

关键词：

2'; 2'-DIFLUORODEOXYCYTIDINE; 5'-TRIPHOSPHATE; ANTITUMOR-ACTIVITY; DOSE-RATE; ACCUMULATION; INFUSION; CANCER; DESIGN; TRIAL; DNA;

D O I：

10.1021/jm901181h

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The design, synthesis, and biological characterization of an orally active prodrug (3) of gemcitabine are described. Additionally, the identification of a novel co-crystal solid form of the compound is presented. Valproate amide 3 is orally bioavailable and releases gemcitabine into the systemic circulation after passing through the intestinal mucosa. The compound has entered clinical trials and is being evaluated as a potential new anticancer agent.

引用

页码：6958 / 6961

页数：4

共 22 条

[1] Phase II trial of a 24-hour infusion of gemcitabine in previously untreated patients with advanced pancreatic adenocarcinoma [J].

Eckel, F ;

Schmelz, R ;

Erdmann, J ;

Mayr, M ;

Lersch, C .

CANCER INVESTIGATION, 2003, 21 (05) :690-694

[2] Pancreatic cancer: a review of recent advances [J].

Eckel, Florian ;

Schneider, Guenter ;

Schmid, Roland M. .

EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2006, 15 (11) :1395-1410

[3] Lessons learned from marketed and investigational prodrugs [J].

Ettmayer, P ;

Amidon, GL ;

Clement, B ;

Testa, B .

JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (10) :2393-2404

[4]

GRUNEWALD R, 1990, CANCER RES, V50, P6823

[5] SATURATION OF 2',2'-DIFLUORODEOXYCYTIDINE 5'-TRIPHOSPHATE ACCUMULATION BY MONONUCLEAR-CELLS DURING A PHASE-I TRIAL OF GEMCITABINE [J].

GRUNEWALD, R ;

ABBRUZZESE, JL ;

TARASSOFF, P ;

PLUNKETT, W .

CANCER CHEMOTHERAPY AND PHARMACOLOGY, 1991, 27 (04) :258-262

[6] Selective protection of 2′,2′-difluorodeoxycytidine (gemcitabine) [J].

Guo, ZW ;

Gallo, JM .

JOURNAL OF ORGANIC CHEMISTRY, 1999, 64 (22) :8319-8322

[7]

HEINEMANN V, 1992, CANCER RES, V52, P533

[8] Gemcitabine in metastatic breast cancer [J].

Heinemann, V .

EXPERT REVIEW OF ANTICANCER THERAPY, 2005, 5 (03) :429-443

[9]

HERTEL LW, 1990, CANCER RES, V50, P4417

[10]

HORTON ND, 2004, M AM ASS CANC RES OR

← 1 2 3 →