Imidazolopiperazines: Hit to Lead Optimization of New Antimalarial Agents

被引：82

作者：

Wu, Tao ^{[1
]}

Nagle, Advait ^{[1
]}

Kuhen, Kelli ^{[1
]}

Gagaring, Kerstin ^{[1
]}

Borboa, Rachel ^{[1
]}

Francek, Caroline ^{[1
]}

Chen, Zhong ^{[1
]}

Plouffe, David ^{[1
]}

Goh, Anne ^{[3
]}

Lakshminarayana, Suresh B. ^{[3
]}

Wu, Jeanette ^{[3
]}

Ang, Hui Qing ^{[3
]}

Zeng, Peiting ^{[3
]}

Kang, Min Low ^{[3
]}

Tan, William ^{[3
]}

Tan, Maria ^{[3
]}

Ye, Nicole ^{[3
]}

Lin, Xuena ^{[5
]}

Caldwell, Christopher ^{[5
]}

Ek, Jared ^{[1
]}

Skolnik, Suzanne ^{[5
]}

Liu, Fenghua ^{[5
]}

Wang, Jianling ^{[5
]}

Chang, Jonathan ^{[1
]}

Li, Chun ^{[1
]}

Hollenbeck, Thomas ^{[1
]}

Tuntland, Tove ^{[1
]}

Isbell, John ^{[1
]}

Fischli, Christoph ^{[2
,4
]}

Brun, Reto ^{[2
,4
]}

Rottmann, Matthias ^{[2
,4
]}

Dartois, Veronique ^{[3
]}

Keller, Thomas ^{[3
]}

Diagana, Thierry ^{[3
]}

Winzeler, Elizabeth ^{[1
]}

Glynne, Richard ^{[1
]}

Tully, David C. ^{[1
]}

Chatterjee, Arnab K. ^{[1
]}

机构：

[1] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA

[2] Swiss Trop & Publ Hlth Inst, CH-4002 Basel, Switzerland

[3] Novartis Inst Trop Dis, Singapore 138670, Singapore

[4] Univ Basel, CH-4003 Basel, Switzerland

[5] Novartis Inst Biomed Res, Preclin Profiling Grp, Cambridge, MA USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 14期

基金：

英国惠康基金;

关键词：

3-COMPONENT CONDENSATION; ANNULATED PYRIDINES; INTRINSIC CLEARANCE; LIVER-MICROSOMES; DRUG DISCOVERY; PATCH-CLAMP; PYRIMIDINES; PYRAZINES; LIBRARY; MALARIA;

D O I：

10.1021/jm2003359

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Starting from a hit series from a GNF compound library collection and based on a cell-based proliferation assay of Plasmodium falciparum, a novel imidazolopiperazine scaffold was optimized. SAR for this series of compounds is discussed, focusing on optimization of cellular potency against wild-type and drug resistant parasites and improvement of physiochemical and pharmacokinetic properties. The lead compounds in this series showed good potencies in vitro and decent oral exposure levels in vivo. In a Plasmodium berghei mouse infection model, one lead compound lowered the parasitemia level by 99.4% after administration of 100 mg/kg single oral dose and prolonged mice survival by an average of 17.0 days. The lead compounds were also well-tolerated in the preliminary in vitro toxicity studies and represents an interesting lead for drug development.

引用

页码：5116 / 5130

页数：15

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