Design and Synthesis of Brain Penetrant Trypanocidal N-Myristoyltransferase Inhibitors

Tracy Bayliss, David Robinson, Victoria Smith, Stephen Brand, Stuart McElroy, Leah Torrie, Chidochangu Mpamhanga, Suzanne Norval, Laste Stojanovski, Ruth Brenk, Julie Frearson, Kevin Read, Ian Gilbert, Paul Wyatt (Lead / Corresponding author)

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Abstract

N-Myristoyltransferase (NMT) represents a promising drug target within the parasitic protozoa Trpanosoma brucei (T. brucei), the causative agent for human African trypanosomiasis (HAT) or sleeping sickness. We have previously validated T. brucei NMT as a promising druggable target for the treatment of HAT in both stage 1 and 2 of the disease. We report on the use of the previously reported DDD85646 (1) as a start point for the design of a class of potent, brain penetrant inhibitors of T. brucei NMT.
Original languageEnglish
Pages (from-to)9790-9806
Number of pages17
JournalJournal of Medicinal Chemistry
Volume60
Issue number23
Early online date10 Nov 2017
DOIs
Publication statusPublished - 14 Dec 2017

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African Trypanosomiasis
Brain
Pharmaceutical Preparations
glycylpeptide N-tetradecanoyltransferase
DDD 85646

Cite this

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title = "Design and Synthesis of Brain Penetrant Trypanocidal N-Myristoyltransferase Inhibitors",
abstract = "N-Myristoyltransferase (NMT) represents a promising drug target within the parasitic protozoa Trpanosoma brucei (T. brucei), the causative agent for human African trypanosomiasis (HAT) or sleeping sickness. We have previously validated T. brucei NMT as a promising druggable target for the treatment of HAT in both stage 1 and 2 of the disease. We report on the use of the previously reported DDD85646 (1) as a start point for the design of a class of potent, brain penetrant inhibitors of T. brucei NMT.",
author = "Tracy Bayliss and David Robinson and Victoria Smith and Stephen Brand and Stuart McElroy and Leah Torrie and Chidochangu Mpamhanga and Suzanne Norval and Laste Stojanovski and Ruth Brenk and Julie Frearson and Kevin Read and Ian Gilbert and Paul Wyatt",
note = "Funding for this work was provided by the Wellcome Trust (Grant Ref. WT077705 and Strategic Award WT083481).",
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Design and Synthesis of Brain Penetrant Trypanocidal N-Myristoyltransferase Inhibitors. / Bayliss, Tracy; Robinson, David; Smith, Victoria; Brand, Stephen; McElroy, Stuart; Torrie, Leah; Mpamhanga, Chidochangu; Norval, Suzanne; Stojanovski, Laste; Brenk, Ruth; Frearson, Julie; Read, Kevin; Gilbert, Ian; Wyatt, Paul (Lead / Corresponding author).

In: Journal of Medicinal Chemistry, Vol. 60, No. 23, 14.12.2017, p. 9790-9806.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Design and Synthesis of Brain Penetrant Trypanocidal N-Myristoyltransferase Inhibitors

AU - Bayliss, Tracy

AU - Robinson, David

AU - Smith, Victoria

AU - Brand, Stephen

AU - McElroy, Stuart

AU - Torrie, Leah

AU - Mpamhanga, Chidochangu

AU - Norval, Suzanne

AU - Stojanovski, Laste

AU - Brenk, Ruth

AU - Frearson, Julie

AU - Read, Kevin

AU - Gilbert, Ian

AU - Wyatt, Paul

N1 - Funding for this work was provided by the Wellcome Trust (Grant Ref. WT077705 and Strategic Award WT083481).

PY - 2017/12/14

Y1 - 2017/12/14

N2 - N-Myristoyltransferase (NMT) represents a promising drug target within the parasitic protozoa Trpanosoma brucei (T. brucei), the causative agent for human African trypanosomiasis (HAT) or sleeping sickness. We have previously validated T. brucei NMT as a promising druggable target for the treatment of HAT in both stage 1 and 2 of the disease. We report on the use of the previously reported DDD85646 (1) as a start point for the design of a class of potent, brain penetrant inhibitors of T. brucei NMT.

AB - N-Myristoyltransferase (NMT) represents a promising drug target within the parasitic protozoa Trpanosoma brucei (T. brucei), the causative agent for human African trypanosomiasis (HAT) or sleeping sickness. We have previously validated T. brucei NMT as a promising druggable target for the treatment of HAT in both stage 1 and 2 of the disease. We report on the use of the previously reported DDD85646 (1) as a start point for the design of a class of potent, brain penetrant inhibitors of T. brucei NMT.

U2 - 10.1021/acs.jmedchem.7b01255

DO - 10.1021/acs.jmedchem.7b01255

M3 - Article

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VL - 60

SP - 9790

EP - 9806

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

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ER -