Structure-Activity Relationship Studies of Orally Active Antimalarial 2,4-Diamino-thienopyrimidines

被引：14

作者：

Cabrera, Diego Gonzalez ^{[1
]}

Douelle, Frederic ^{[1
]}

Le Manach, Claire ^{[1
]}

Han, Ze ^{[1
]}

Paquet, Tanya ^{[1
]}

Taylor, Dale ^{[2
]}

Njoroge, Mathew ^{[2
]}

Lawrence, Nina ^{[2
]}

Wiesner, Lubbe ^{[2
,6
]}

Waterson, David ^{[3
]}

Witty, Michael J. ^{[3
]}

Wittlin, Sergio ^{[4
,5
]}

Street, Leslie J. ^{[1
]}

Chibale, Kelly ^{[1
,6
,7
]}

机构：

[1] Univ Cape Town, Drug Discovery & Dev Ctr H3D, Dept Chem, ZA-7701 Cape Town, South Africa

[2] Univ Cape Town, Div Clin Pharmacol, Dept Med, ZA-7925 Cape Town, South Africa

[3] ICC, Med Malaria Venture, CH-1215 Geneva, Switzerland

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

[5] Univ Basel, CH-4002 Basel, Switzerland

[6] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7701 Cape Town, South Africa

[7] Univ Cape Town, South African Med Res Council, Drug Discovery & Dev Res Unit, ZA-7701 Cape Town, South Africa

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 18期

基金：

英国医学研究理事会;

关键词：

CROSS-COUPLING REACTIONS; DRUG DISCOVERY; ARYL HALIDES; ERADICATION; SNAPSHOT; MALARIA; PK;

D O I：

10.1021/acs.jmedchem.5b01156

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Based on the initial optimization of orally active antimalarial 2,4-diamino-thienopyrimidines and with the help of metabolite identification studies, a second generation of derivatives involving changes at the 2- and 4-positions of the thienopyrimidine core were synthesized. Improvements in the physiochemical properties resulted in the identification of 15a, 17a, 32, and 40 as lead molecules with improved in vivo exposure. Furthermore, analogue 40 exhibited excellent in vivo antimalarial activity when dosed orally at 50 mg/kg once daily for 4 days in the Plasmodium berghei mouse model, which is superior to the activity seen with previously reported compounds, and with a slightly improved hERG profile.

引用

页码：7572 / 7579

页数：8

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