Novel heteroaromatic organofluorine inhibitors of fructose-1,6-bisphosphatase.
A broad group of compounds including substituted pyrazoles, pyrroles, indoles, and carbazoles were screened to identify potential inhibitor lead compounds of fructose-1,6-bisphosphatase (FBPase). Best inhibitors are (1H-indol-1-yl)(4-(trifluoromethyl)phenyl)methanone, ethyl 3-(3,5-dimethyl-1H-pyrrol-2-yl)-4,4,4-trifluoro-3-hydroxybutanoate, 3,5-diphenyl-1-(3-(trifluoromethyl) phenyl)-1H-pyrazole, and ethyl 3,3,3-trifluoro-2-hydroxy-2-(1-methyl-1H-indol-3-yl)propanoate. The IC50 values (3.1, 4.8, 6.1, and 11.9 microM) were comparable to that of AMP, the natural inhibitor of murine FBPase (IC50 of 4.0 microM). Docking programs were utilized to interpret the experiments.
Rudnitskaya
Aleksandra
A
Department of Chemistry, University of Massachusetts, Boston, Massachusetts 02125, USA.
Huynh
Ken
K
Török
Béla
B
Stieglitz
Kimberly
K
D000249:Adenosine Monophosphate / Q000378:metabolism; D000818:Animals; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D005461:Fluorine / Q000494:pharmacology*; D006597:Fructose-Bisphosphatase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D051379:Mice; D011720:Pyrazoles / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007211:Indoles; D011720:Pyrazoles; D005461:Fluorine; D000249:Adenosine Monophosphate; D006597:Fructose-Bisphosphatase