title: Prodrug thiamine analogs as inhibitors of the enzyme transketolase.
abstract: 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.
authors: Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA. yhuerou@arraybiopharma.com
authors: Yvan
authors: Y
authors: Le Huerou
authors: Indrani
authors: I
authors: Gunawardana
authors: Allen A
authors: AA
authors: Thomas
authors: Steven A
authors: SA
authors: Boyd
authors: Jason
authors: J
authors: de Meese
authors: Walter
authors: W
authors: Dewolf
authors: Steven S
authors: SS
authors: Gonzales
authors: May
authors: M
authors: Han
authors: Laura
authors: L
authors: Hayter
authors: Tomas
authors: T
authors: Kaplan
authors: Christine
authors: C
authors: Lemieux
authors: Patrice
authors: P
authors: Lee
authors: Jed
authors: J
authors: Pheneger
authors: Gregory
authors: G
authors: Poch
authors: Todd T
authors: TT
authors: Romoff
authors: Francis
authors: F
authors: Sullivan
authors: Solly
authors: S
authors: Weiler
authors: S Kirk
authors: SK
authors: Wright
authors: Jie
authors: J
authors: Lin
mesh_terms: 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*
chemical_list: D004791:Enzyme Inhibitors; D011355:Prodrugs; D014174:Transketolase; D013831:Thiamine