Discovery of a quinoline-4-carboxamide derivative with a novel mechanism of action, multistage antimalarial activity, and potent in vivo efficacy

Beatriz Baragaña, Neil R. Norcross, Caroline Wilson, Achim Porzelle, Irene Hallyburton, Raffaella Grimaldi, Maria Osuna-Cabello, Suzanne Norval, Jennifer Riley, Laste Stojanovski, Frederick R. C. Simeons, Paul G. Wyatt, Michael J. Delves, Stephan Meister, Sandra Duffy, Vicky M. Avery, Elizabeth A. Winzeler, Robert E. Sinden, Sergio Wittlin, Julie A. FrearsonDavid W. Gray, Alan H. Fairlamb, David Waterson, Simon F. Campbell, Paul Willis, Kevin D. Read, Ian H. Gilbert

Research output: Contribution to journalArticle

21 Citations (Scopus)
114 Downloads (Pure)

Abstract

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.

Original languageEnglish
Pages (from-to)9672-9685
Number of pages14
JournalJournal of Medicinal Chemistry
Volume59
Issue number21
Early online date10 Sep 2016
DOIs
Publication statusPublished - 10 Nov 2016

Fingerprint

Peptide Elongation Factor 2
Antimalarials
Plasmodium falciparum
Malaria
Pharmacokinetics
quinoline
In Vitro Techniques
DDD107498

Cite this

Baragaña, Beatriz ; Norcross, Neil R. ; Wilson, Caroline ; Porzelle, Achim ; Hallyburton, Irene ; Grimaldi, Raffaella ; Osuna-Cabello, Maria ; Norval, Suzanne ; Riley, Jennifer ; Stojanovski, Laste ; Simeons, Frederick R. C. ; Wyatt, Paul G. ; Delves, Michael J. ; Meister, Stephan ; Duffy, Sandra ; Avery, Vicky M. ; Winzeler, Elizabeth A. ; Sinden, Robert E. ; Wittlin, Sergio ; Frearson, Julie A. ; Gray, David W. ; Fairlamb, Alan H. ; Waterson, David ; Campbell, Simon F. ; Willis, Paul ; Read, Kevin D. ; Gilbert, Ian H. / Discovery of a quinoline-4-carboxamide derivative with a novel mechanism of action, multistage antimalarial activity, and potent in vivo efficacy. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 21. pp. 9672-9685.
@article{17a2501a8d1641648aa0c87871532893,
title = "Discovery of a quinoline-4-carboxamide derivative with a novel mechanism of action, multistage antimalarial activity, and potent in vivo efficacy",
abstract = "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.",
author = "Beatriz Baraga{\~n}a and Norcross, {Neil R.} and Caroline Wilson and Achim Porzelle and Irene Hallyburton and Raffaella Grimaldi and Maria Osuna-Cabello and Suzanne Norval and Jennifer Riley and Laste Stojanovski and Simeons, {Frederick R. C.} and Wyatt, {Paul G.} and Delves, {Michael J.} and Stephan Meister and Sandra Duffy and Avery, {Vicky M.} and Winzeler, {Elizabeth A.} and Sinden, {Robert E.} and Sergio Wittlin and Frearson, {Julie A.} and Gray, {David W.} and Fairlamb, {Alan H.} and David Waterson and Campbell, {Simon F.} and Paul Willis and Read, {Kevin D.} and Gilbert, {Ian H.}",
note = "We acknowledge Medicines for Malaria Venture for financial support. The University of Dundee also acknowledges support from the Wellcome Trust (Grant 100476 and a Principal Research Fellowship to A.H.F.)",
year = "2016",
month = "11",
day = "10",
doi = "10.1021/acs.jmedchem.6b00723",
language = "English",
volume = "59",
pages = "9672--9685",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "21",

}

Baragaña, B, Norcross, NR, Wilson, C, Porzelle, A, Hallyburton, I, Grimaldi, R, Osuna-Cabello, M, Norval, S, Riley, J, Stojanovski, L, Simeons, FRC, Wyatt, PG, Delves, MJ, Meister, S, Duffy, S, Avery, VM, Winzeler, EA, Sinden, RE, Wittlin, S, Frearson, JA, Gray, DW, Fairlamb, AH, Waterson, D, Campbell, SF, Willis, P, Read, KD & Gilbert, IH 2016, 'Discovery of a quinoline-4-carboxamide derivative with a novel mechanism of action, multistage antimalarial activity, and potent in vivo efficacy', Journal of Medicinal Chemistry, vol. 59, no. 21, pp. 9672-9685. https://doi.org/10.1021/acs.jmedchem.6b00723

Discovery of a quinoline-4-carboxamide derivative with a novel mechanism of action, multistage antimalarial activity, and potent in vivo efficacy. / Baragaña, Beatriz; Norcross, Neil R.; Wilson, Caroline; Porzelle, Achim; Hallyburton, Irene; Grimaldi, Raffaella; Osuna-Cabello, Maria; Norval, Suzanne; Riley, Jennifer; Stojanovski, Laste; Simeons, Frederick R. C.; Wyatt, Paul G.; Delves, Michael J.; Meister, Stephan; Duffy, Sandra; Avery, Vicky M.; Winzeler, Elizabeth A.; Sinden, Robert E.; Wittlin, Sergio; Frearson, Julie A.; Gray, David W.; Fairlamb, Alan H.; Waterson, David; Campbell, Simon F.; Willis, Paul; Read, Kevin D. (Lead / Corresponding author); Gilbert, Ian H. (Lead / Corresponding author).

In: Journal of Medicinal Chemistry, Vol. 59, No. 21, 10.11.2016, p. 9672-9685.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Discovery of a quinoline-4-carboxamide derivative with a novel mechanism of action, multistage antimalarial activity, and potent in vivo efficacy

AU - Baragaña, Beatriz

AU - Norcross, Neil R.

AU - Wilson, Caroline

AU - Porzelle, Achim

AU - Hallyburton, Irene

AU - Grimaldi, Raffaella

AU - Osuna-Cabello, Maria

AU - Norval, Suzanne

AU - Riley, Jennifer

AU - Stojanovski, Laste

AU - Simeons, Frederick R. C.

AU - Wyatt, Paul G.

AU - Delves, Michael J.

AU - Meister, Stephan

AU - Duffy, Sandra

AU - Avery, Vicky M.

AU - Winzeler, Elizabeth A.

AU - Sinden, Robert E.

AU - Wittlin, Sergio

AU - Frearson, Julie A.

AU - Gray, David W.

AU - Fairlamb, Alan H.

AU - Waterson, David

AU - Campbell, Simon F.

AU - Willis, Paul

AU - Read, Kevin D.

AU - Gilbert, Ian H.

N1 - We acknowledge Medicines for Malaria Venture for financial support. The University of Dundee also acknowledges support from the Wellcome Trust (Grant 100476 and a Principal Research Fellowship to A.H.F.)

PY - 2016/11/10

Y1 - 2016/11/10

N2 - 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.

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.

U2 - 10.1021/acs.jmedchem.6b00723

DO - 10.1021/acs.jmedchem.6b00723

M3 - Article

C2 - 27631715

VL - 59

SP - 9672

EP - 9685

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 21

ER -