Prodrug thiamine analogs as inhibitors of the enzyme transketolase.
Transketolase, a key enzyme in the pentose phosphate pathway, has been suggested as a target for inhibition in the treatment of cancer. Compound 5a ('N3'-pyridyl thiamine'; 3-(6-methyl-2-amino-pyridin-3-ylmethyl)-5-(2-hydroxy-ethyl)-4-methyl-thiazol-3-ium chloride hydrochloride), an analog of the transketolase cofactor thiamine, is a potent transketolase inhibitor but suffers from poor pharmacokinetics due to high clearance and C(max) linked toxicity. An efficient way of improving the pharmacokinetic profile of 5a is to prepare oxidized prodrugs which are slowly reduced in vivo yielding longer, sustained blood levels of the drug. The synthesis of such prodrugs and their evaluation in rodent models is reported.
Le Huerou
Yvan
Y
Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA. yhuerou@arraybiopharma.com
Gunawardana
Indrani
I
Thomas
Allen A
AA
Boyd
Steven A
SA
de Meese
Jason
J
Dewolf
Walter
W
Gonzales
Steven S
SS
Han
May
M
Hayter
Laura
L
Kaplan
Tomas
T
Lemieux
Christine
C
Lee
Patrice
P
Pheneger
Jed
J
Poch
Gregory
G
Romoff
Todd T
TT
Sullivan
Francis
F
Weiler
Solly
S
Wright
S Kirk
SK
Lin
Jie
J
D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015394:Molecular Structure; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013831:Thiamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D014174:Transketolase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D011355:Prodrugs; D014174:Transketolase; D013831:Thiamine