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Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors

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Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors. / Brand, Stephen; Cleghorn, Laura A. T.; McElroy, Stuart P.; Robinson, David A.; Smith, Victoria C.; Hallyburton, Irene; Harrison, Justin R.; Norcross, Neil R.; Spinks, Daniel; Bayliss, Tracy; Norval, Suzanne; Stojanovski, Laste; Torrie, Leah S.; Frearson, Julie A.; Brenk, Ruth; Fairlamb, Alan H.; Ferguson, Michael A. J.; Read, Kevin D.; Wyatt, Paul G.; Gilbert, Ian H. (Lead / Corresponding author).

In: Journal of Medicinal Chemistry, Vol. 55, No. 1, 12.01.2012, p. 140-152.

Research output: Contribution to journalArticle

Harvard

Brand, S, Cleghorn, LAT, McElroy, SP, Robinson, DA, Smith, VC, Hallyburton, I, Harrison, JR, Norcross, NR, Spinks, D, Bayliss, T, Norval, S, Stojanovski, L, Torrie, LS, Frearson, JA, Brenk, R, Fairlamb, AH, Ferguson, MAJ, Read, KD, Wyatt, PG & Gilbert, IH 2012, 'Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors' Journal of Medicinal Chemistry, vol 55, no. 1, pp. 140-152., 10.1021/jm201091t

APA

Brand, S., Cleghorn, L. A. T., McElroy, S. P., Robinson, D. A., Smith, V. C., Hallyburton, I., ... Gilbert, I. H. (2012). Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors. Journal of Medicinal Chemistry, 55(1), 140-152. 10.1021/jm201091t

Vancouver

Brand S, Cleghorn LAT, McElroy SP, Robinson DA, Smith VC, Hallyburton I et al. Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors. Journal of Medicinal Chemistry. 2012 Jan 12;55(1):140-152. Available from: 10.1021/jm201091t

Author

Brand, Stephen; Cleghorn, Laura A. T.; McElroy, Stuart P.; Robinson, David A.; Smith, Victoria C.; Hallyburton, Irene; Harrison, Justin R.; Norcross, Neil R.; Spinks, Daniel; Bayliss, Tracy; Norval, Suzanne; Stojanovski, Laste; Torrie, Leah S.; Frearson, Julie A.; Brenk, Ruth; Fairlamb, Alan H.; Ferguson, Michael A. J.; Read, Kevin D.; Wyatt, Paul G.; Gilbert, Ian H. (Lead / Corresponding author) / Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors.

In: Journal of Medicinal Chemistry, Vol. 55, No. 1, 12.01.2012, p. 140-152.

Research output: Contribution to journalArticle

Bibtex - Download

@article{0901640bb51e4183be5c0beb292aab5c,
title = "Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors",
keywords = "CANDIDA-ALBICANS, TRYPANOSOMA-BRUCEI, DRUG DISCOVERY, PEPTIDOMIMETIC INHIBITORS, SELECTIVE INHIBITORS, DIPEPTIDE AMIDES, PROTEIN, DESIGN, POTENT, BENZOFURANS",
author = "Stephen Brand and Cleghorn, {Laura A. T.} and McElroy, {Stuart P.} and Robinson, {David A.} and Smith, {Victoria C.} and Irene Hallyburton and Harrison, {Justin R.} and Norcross, {Neil R.} and Daniel Spinks and Tracy Bayliss and Suzanne Norval and Laste Stojanovski and Torrie, {Leah S.} and Frearson, {Julie A.} and Ruth Brenk and Fairlamb, {Alan H.} and Ferguson, {Michael A. J.} and Read, {Kevin D.} and Wyatt, {Paul G.} and Gilbert, {Ian H.}",
year = "2012",
doi = "10.1021/jm201091t",
volume = "55",
number = "1",
pages = "140--152",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors

A1 - Brand,Stephen

A1 - Cleghorn,Laura A. T.

A1 - McElroy,Stuart P.

A1 - Robinson,David A.

A1 - Smith,Victoria C.

A1 - Hallyburton,Irene

A1 - Harrison,Justin R.

A1 - Norcross,Neil R.

A1 - Spinks,Daniel

A1 - Bayliss,Tracy

A1 - Norval,Suzanne

A1 - Stojanovski,Laste

A1 - Torrie,Leah S.

A1 - Frearson,Julie A.

A1 - Brenk,Ruth

A1 - Fairlamb,Alan H.

A1 - Ferguson,Michael A. J.

A1 - Read,Kevin D.

A1 - Wyatt,Paul G.

A1 - Gilbert,Ian H.

AU - Brand,Stephen

AU - Cleghorn,Laura A. T.

AU - McElroy,Stuart P.

AU - Robinson,David A.

AU - Smith,Victoria C.

AU - Hallyburton,Irene

AU - Harrison,Justin R.

AU - Norcross,Neil R.

AU - Spinks,Daniel

AU - Bayliss,Tracy

AU - Norval,Suzanne

AU - Stojanovski,Laste

AU - Torrie,Leah S.

AU - Frearson,Julie A.

AU - Brenk,Ruth

AU - Fairlamb,Alan H.

AU - Ferguson,Michael A. J.

AU - Read,Kevin D.

AU - Wyatt,Paul G.

AU - Gilbert,Ian H.

PY - 2012/1/12

Y1 - 2012/1/12

N2 - <p>N-Myristoyltransferase (NMT) represents a promising drug target for human African trypanosomiasis (HAT), which is caused by the parasitic protozoa Trypanosoma brucei. We report the optimization of a high throughput screening hit (1) to give a lead molecule DDD85646 (63), which has potent activity against the enzyme (IC50 = 2 nM) and T. brucei (EC50 = 2 nM) in culture. The compound has good oral pharmacokinetics and cures rodent models of peripheral HAT infection. This compound provides an excellent tool for validation of T. brucei NMT as a drug target for HAT as well as a valuable lead for further optimization.</p>

AB - <p>N-Myristoyltransferase (NMT) represents a promising drug target for human African trypanosomiasis (HAT), which is caused by the parasitic protozoa Trypanosoma brucei. We report the optimization of a high throughput screening hit (1) to give a lead molecule DDD85646 (63), which has potent activity against the enzyme (IC50 = 2 nM) and T. brucei (EC50 = 2 nM) in culture. The compound has good oral pharmacokinetics and cures rodent models of peripheral HAT infection. This compound provides an excellent tool for validation of T. brucei NMT as a drug target for HAT as well as a valuable lead for further optimization.</p>

KW - CANDIDA-ALBICANS

KW - TRYPANOSOMA-BRUCEI

KW - DRUG DISCOVERY

KW - PEPTIDOMIMETIC INHIBITORS

KW - SELECTIVE INHIBITORS

KW - DIPEPTIDE AMIDES

KW - PROTEIN

KW - DESIGN

KW - POTENT

KW - BENZOFURANS

UR - http://ukpmc.ac.uk/articles/PMC3256935

UR - http://www.scopus.com/inward/record.url?scp=84855848964&partnerID=8YFLogxK

U2 - 10.1021/jm201091t

DO - 10.1021/jm201091t

M1 - Article

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 1

VL - 55

SP - 140

EP - 152

ER -

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    4 MB, PDF-document

    Reprinted with permission from Brand, S, Cleghorn, LAT, McElroy, SP, Robinson, DA, Smith, VC, Hallyburton, I, Harrison, JR, Norcross, NR, Spinks, D, Bayliss, T, Norval, S, Stojanovski, L, Torrie, LS, Frearson, JA, Brenk, R, Fairlamb, AH, Ferguson, MAJ, Read, KD, Wyatt, PG & Gilbert, IH 2012, 'Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors' Journal of Medicinal Chemistry, vol 55, no. 1, pp. 140-152.. Copyright 2012 American Chemical Society.

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