Imperial College London
Alternate

Emeritus ProfessorRobertSinden

Faculty of Natural Sciences, Department of Life Sciences

Emeritus Professor of Parasite Cell Biology
 
 
 
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Contact

 

r.sinden Website

 
 
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Location

 

2.1Centre for Population BiologySilwood Park

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Summary

 

Publications

Citation

BibTex format

@article{Baragaña:2016:10.1021/acs.jmedchem.6b00723,
author = {Baragaña, B and Norcross, NR and Wilson, C and Porzelle, A and Hallyburton, I and Grimaldi, R and Osuna-Cabello, M and Norval, S and Riley, J and Stojanovski, L and Simeons, FR and Wyatt, PG and Delves, MJ and Meister, S and Duffy, S and Avery, VM and Winzeler, EA and Sinden, RE and Wittlin, S and Frearson, JA and Gray, DW and Fairlamb, AH and Waterson, D and Campbell, SF and Willis, P and Read, KD and Gilbert, IH},
doi = {10.1021/acs.jmedchem.6b00723},
journal = {Journal of Medicinal Chemistry},
pages = {9672--9685},
title = {Discovery of a quinoline-4-carboxamide derivative with a novel mechanism of action, multistage antimalarial activity, and potent in vivo efficacy},
url = {http://dx.doi.org/10.1021/acs.jmedchem.6b00723},
volume = {59},
year = {2016}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - The antiplasmodial activity, DMPK properties, and efficacy of a series of quinoline-4-carboxamides are described. This series was identified from a phenotypic screen against the blood stage of Plasmodium falciparum (3D7) and displayed moderate potency but with suboptimal physicochemical properties and poor microsomal stability. The screening hit (1, EC50 = 120 nM) was optimized to lead molecules with low nanomolar in vitro potency. Improvement of the pharmacokinetic profile led to several compounds showing excellent oral efficacy in the P. berghei malaria mouse model with ED90 values below 1 mg/kg when dosed orally for 4 days. The favorable potency, selectivity, DMPK properties, and efficacy coupled with a novel mechanism of action, inhibition of translation elongation factor 2 (PfEF2), led to progression of 2 (DDD107498) to preclinical development.
AU  - Baragaña,B
AU  - Norcross,NR
AU  - Wilson,C
AU  - Porzelle,A
AU  - Hallyburton,I
AU  - Grimaldi,R
AU  - Osuna-Cabello,M
AU  - Norval,S
AU  - Riley,J
AU  - Stojanovski,L
AU  - Simeons,FR
AU  - Wyatt,PG
AU  - Delves,MJ
AU  - Meister,S
AU  - Duffy,S
AU  - Avery,VM
AU  - Winzeler,EA
AU  - Sinden,RE
AU  - Wittlin,S
AU  - Frearson,JA
AU  - Gray,DW
AU  - Fairlamb,AH
AU  - Waterson,D
AU  - Campbell,SF
AU  - Willis,P
AU  - Read,KD
AU  - Gilbert,IH
DO  - 10.1021/acs.jmedchem.6b00723
EP  - 9685
PY  - 2016///
SN  - 0022-2623
SP  - 9672
TI  - Discovery of a quinoline-4-carboxamide derivative with a novel mechanism of action, multistage antimalarial activity, and potent in vivo efficacy
T2  - Journal of Medicinal Chemistry
UR  - http://dx.doi.org/10.1021/acs.jmedchem.6b00723
UR  - http://hdl.handle.net/10044/1/40852
VL  - 59
ER  -
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