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
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://www.scopus.com/inward/record.url?scp=84855848964&partnerID=8YFLogxK
U2 - 10.1021/jm201091t
DO - 10.1021/jm201091t
M3 - Article
VL - 55
SP - 140
EP - 152
JO - Journal of Medicinal Chemistry
T2 - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 1
ER -
Final published version, 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.
Final published version