Medicinal chemistry optimization of antiplasmodial imidazopyridazine hits from high throughput screening of a SoftFocus kinase library: Part 1

Claire Le Manach, Diego Gonzalez Cabrera, Frederic Douelle, Aloysius T Nchinda, Yassir Younis, Dale Taylor, Lubbe Wiesner, Karen Louise White, Eileen Ryan, Corinne March, Sandra Duffy, Vicky M Avery, David Waterson, Michael J Witty, Sergio Wittlin, Susan Ann Charman, Leslie J Street, Kelly Chibale

Research output: Contribution to journalArticleResearchpeer-review

Abstract

A novel class of imidazopyridazines identified from whole cell screening of a SoftFocus kinase library was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant strain) and NF54 (sensitive strain). Structure-activity relationship studies led to the identification of highly potent compounds against both strains. Compound 35 was highly active (IC 50: K1 = 6.3 nM, NF54 = 7.3 nM) and comparable in potency to artesunate, and 35 exhibited 98 activity in the in vivo P. berghei mouse model (4-day test by Peters) at 4 ? 50 mg/kg po. Compound 35 was also assessed against P. falciparum in the in vivo SCID mouse model where the efficacy was found to be more consistent with the in vitro activity. Furthermore, 35 displayed high (78 ) rat oral bioavailability with good oral exposure and plasma half-life. Mice exposure at the same dose was 10-fold lower than in rat, suggesting lower oral absorption and/or higher metabolic clearance in mice.
Original languageEnglish
Pages (from-to)2789 - 2798
Number of pages10
JournalJournal of Medicinal Chemistry
Volume57
Issue number6
DOIs
Publication statusPublished - 2014

Cite this

Le Manach, Claire ; Cabrera, Diego Gonzalez ; Douelle, Frederic ; Nchinda, Aloysius T ; Younis, Yassir ; Taylor, Dale ; Wiesner, Lubbe ; White, Karen Louise ; Ryan, Eileen ; March, Corinne ; Duffy, Sandra ; Avery, Vicky M ; Waterson, David ; Witty, Michael J ; Wittlin, Sergio ; Charman, Susan Ann ; Street, Leslie J ; Chibale, Kelly. / Medicinal chemistry optimization of antiplasmodial imidazopyridazine hits from high throughput screening of a SoftFocus kinase library: Part 1. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 6. pp. 2789 - 2798.
@article{b2415b02d0644ebbb3022577a1c6975e,
title = "Medicinal chemistry optimization of antiplasmodial imidazopyridazine hits from high throughput screening of a SoftFocus kinase library: Part 1",
abstract = "A novel class of imidazopyridazines identified from whole cell screening of a SoftFocus kinase library was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant strain) and NF54 (sensitive strain). Structure-activity relationship studies led to the identification of highly potent compounds against both strains. Compound 35 was highly active (IC 50: K1 = 6.3 nM, NF54 = 7.3 nM) and comparable in potency to artesunate, and 35 exhibited 98 activity in the in vivo P. berghei mouse model (4-day test by Peters) at 4 ? 50 mg/kg po. Compound 35 was also assessed against P. falciparum in the in vivo SCID mouse model where the efficacy was found to be more consistent with the in vitro activity. Furthermore, 35 displayed high (78 ) rat oral bioavailability with good oral exposure and plasma half-life. Mice exposure at the same dose was 10-fold lower than in rat, suggesting lower oral absorption and/or higher metabolic clearance in mice.",
author = "{Le Manach}, Claire and Cabrera, {Diego Gonzalez} and Frederic Douelle and Nchinda, {Aloysius T} and Yassir Younis and Dale Taylor and Lubbe Wiesner and White, {Karen Louise} and Eileen Ryan and Corinne March and Sandra Duffy and Avery, {Vicky M} and David Waterson and Witty, {Michael J} and Sergio Wittlin and Charman, {Susan Ann} and Street, {Leslie J} and Kelly Chibale",
year = "2014",
doi = "10.1021/jm500098s",
language = "English",
volume = "57",
pages = "2789 -- 2798",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "AMER CHEMICAL SOC",
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}

Le Manach, C, Cabrera, DG, Douelle, F, Nchinda, AT, Younis, Y, Taylor, D, Wiesner, L, White, KL, Ryan, E, March, C, Duffy, S, Avery, VM, Waterson, D, Witty, MJ, Wittlin, S, Charman, SA, Street, LJ & Chibale, K 2014, 'Medicinal chemistry optimization of antiplasmodial imidazopyridazine hits from high throughput screening of a SoftFocus kinase library: Part 1' Journal of Medicinal Chemistry, vol. 57, no. 6, pp. 2789 - 2798. https://doi.org/10.1021/jm500098s

Medicinal chemistry optimization of antiplasmodial imidazopyridazine hits from high throughput screening of a SoftFocus kinase library: Part 1. / Le Manach, Claire; Cabrera, Diego Gonzalez; Douelle, Frederic; Nchinda, Aloysius T; Younis, Yassir; Taylor, Dale; Wiesner, Lubbe; White, Karen Louise; Ryan, Eileen; March, Corinne; Duffy, Sandra; Avery, Vicky M; Waterson, David; Witty, Michael J; Wittlin, Sergio; Charman, Susan Ann; Street, Leslie J; Chibale, Kelly.

In: Journal of Medicinal Chemistry, Vol. 57, No. 6, 2014, p. 2789 - 2798.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Medicinal chemistry optimization of antiplasmodial imidazopyridazine hits from high throughput screening of a SoftFocus kinase library: Part 1

AU - Le Manach, Claire

AU - Cabrera, Diego Gonzalez

AU - Douelle, Frederic

AU - Nchinda, Aloysius T

AU - Younis, Yassir

AU - Taylor, Dale

AU - Wiesner, Lubbe

AU - White, Karen Louise

AU - Ryan, Eileen

AU - March, Corinne

AU - Duffy, Sandra

AU - Avery, Vicky M

AU - Waterson, David

AU - Witty, Michael J

AU - Wittlin, Sergio

AU - Charman, Susan Ann

AU - Street, Leslie J

AU - Chibale, Kelly

PY - 2014

Y1 - 2014

N2 - A novel class of imidazopyridazines identified from whole cell screening of a SoftFocus kinase library was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant strain) and NF54 (sensitive strain). Structure-activity relationship studies led to the identification of highly potent compounds against both strains. Compound 35 was highly active (IC 50: K1 = 6.3 nM, NF54 = 7.3 nM) and comparable in potency to artesunate, and 35 exhibited 98 activity in the in vivo P. berghei mouse model (4-day test by Peters) at 4 ? 50 mg/kg po. Compound 35 was also assessed against P. falciparum in the in vivo SCID mouse model where the efficacy was found to be more consistent with the in vitro activity. Furthermore, 35 displayed high (78 ) rat oral bioavailability with good oral exposure and plasma half-life. Mice exposure at the same dose was 10-fold lower than in rat, suggesting lower oral absorption and/or higher metabolic clearance in mice.

AB - A novel class of imidazopyridazines identified from whole cell screening of a SoftFocus kinase library was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant strain) and NF54 (sensitive strain). Structure-activity relationship studies led to the identification of highly potent compounds against both strains. Compound 35 was highly active (IC 50: K1 = 6.3 nM, NF54 = 7.3 nM) and comparable in potency to artesunate, and 35 exhibited 98 activity in the in vivo P. berghei mouse model (4-day test by Peters) at 4 ? 50 mg/kg po. Compound 35 was also assessed against P. falciparum in the in vivo SCID mouse model where the efficacy was found to be more consistent with the in vitro activity. Furthermore, 35 displayed high (78 ) rat oral bioavailability with good oral exposure and plasma half-life. Mice exposure at the same dose was 10-fold lower than in rat, suggesting lower oral absorption and/or higher metabolic clearance in mice.

UR - http://pubs.acs.org/doi/pdf/10.1021/jm500098s

U2 - 10.1021/jm500098s

DO - 10.1021/jm500098s

M3 - Article

VL - 57

SP - 2789

EP - 2798

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 6

ER -