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. Frearson; David W. Gray; Alan H. Fairlamb; David Waterson; Simon F. Campbell; Paul Willis; Kevin D. Read; Ian H. Gilbert

doi: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

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 (Lead / Corresponding author), Ian H. Gilbert (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

69 Citations (Scopus)

297 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 language	English
Pages (from-to)	9672-9685
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	21
Early online date	10 Sept 2016
DOIs	https://doi.org/10.1021/acs.jmedchem.6b00723
Publication status	Published - 10 Nov 2016

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1021/acs.jmedchem.6b00723Licence: CC BY

Final Published Version
ACS Editors' Choice - This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 1.73 MBLicence: CC BY

A Translational Engine for Biomedical Discoveries (Strategic Grant)
Fairlamb, A. (Investigator) & Gilbert, I. (Investigator)
1/01/13 → 30/09/15
Project: Research

Gilbert, Ian
- Drug Discovery Unit - Professor/Head of the Drug Discovery Unit & Roscoe Chair in Drug Discovery
Person: Academic

Cite this

Baragaña, B., Norcross, N. R., Wilson, C., Porzelle, A., Hallyburton, I., Grimaldi, R., Osuna-Cabello, M., Norval, S., Riley, J., Stojanovski, L., Simeons, F. R. C., Wyatt, P. G., Delves, M. J., Meister, S., Duffy, S., Avery, V. M., Winzeler, E. A., Sinden, R. E., Wittlin, S., ... Gilbert, I. H. (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, 59(21), 9672-9685. https://doi.org/10.1021/acs.jmedchem.6b00723

@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 = nov,

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

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

SN - 0022-2623

VL - 59

SP - 9672

EP - 9685

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 21

ER -

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

Abstract

UN SDGs

Access to Document

Fingerprint

Projects

A Translational Engine for Biomedical Discoveries (Strategic Grant)

Profiles

Gilbert, Ian

Cite this