Novel 2-phenylquinolin-7-yl-derived imidazo[1,5-a]pyrazines as potent insulin-like growth factor-I receptor (IGF-IR) inhibitors

被引：63

作者：

Mulvihill, Mark J. ^{[1
]}

Ji, Qun-Sheng ^{[1
]}

Coate, Heather R. ^{[1
]}

Cooke, Andrew ^{[1
]}

Dong, Hanqing ^{[1
]}

Feng, Lixin ^{[1
]}

Foreman, Kenneth ^{[1
]}

Rosenfeld-Franklin, Maryland ^{[1
]}

Honda, Ayako ^{[1
]}

Mak, Gilda ^{[1
]}

Mulvihill, Kristen M. ^{[1
]}

Nigro, Anthony I. ^{[1
]}

O'Connor, Matthew ^{[1
]}

Pirrit, Caroline ^{[1
]}

Steinig, Arno G. ^{[1
]}

Siu, Kam ^{[1
]}

Stolz, Kathryn M. ^{[1
]}

Sun, Yingchuan ^{[1
]}

Tavares, Paula A. R. ^{[1
]}

Yao, Yan ^{[1
]}

Gibson, Neil W. ^{[1
]}

机构：

[1] OSI Pharmaceut Inc, OSI Oncol, Melville, NY 11747 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2008年 / 16卷 / 03期

关键词：

imidazopyrazines; insulin-like growth factor-I receptor; IGF-IR; tyrosine kinase inhibitor; tumor growth inhibition; cancer;

D O I：

10.1016/j.bmc.2007.10.061

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：

A series of novel, potent quinolinyl-derived imidazo[1,5-a]pyrazine IGF-IR (IGF-1R) inhibitors most notably, cis-3-(3-azetidin-1-ylmethylcyclobutyl)-1-(2-plienylquinotin-7-yl)imidazo[1,5-a]pyrazin-8-ylamine (AQIP)-is described. Synthetic details, structure-activity relationships, and in vitro biological activity are reported for the series. Key in vitro and in vivo biological results for AQIP are reported, including: inhibition of ligand-stimulated autophosphorylation of IGF-IR and downstream pathways in 3T3/huIGFIR cells; inhibition of proliferation and induction of DNA fragmentation in human tumor cell lines; a pharmacokinetic profile suitable for once-per-day oral dosing; antitumor activity in a 3T3/huIGFIR xenograft model; and effects on insulin and glucose levels. (C) 2007 Elsevier Ltd. All rights reserved.

引用

页码：1359 / 1375

页数：17

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