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 journal › Article
}
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
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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