Design and synthesis of pyrazole derivatives as potent and selective inhibitors of tissue-nonspecific alkaline phosphatase (TNAP).
Tissue-nonspecific alkaline phosphatase (TNAP) plays a central role in regulating extracellular matrix calcification during bone formation and growth. High-throughput screening (HTS) for small molecule TNAP inhibitors led to the identification of hits in the sub-micromolar potency range. We report the design, synthesis and in vitro evaluation of a series of pyrazole derivatives of a screening hit which are potent TNAP inhibitors exhibiting IC(50) values as low as 5nM. A representative of the series was characterized in kinetic studies and determined to have a mode of inhibition not previously observed for TNAP inhibitors.
Sidique
Shyama
S
Burnham Center for Chemical Genomics, Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Ardecky
Robert
R
Su
Ying
Y
Narisawa
Sonoko
S
Brown
Brock
B
Millán
José Luis
JL
Sergienko
Eduard
E
Cosford
Nicholas D P
ND
D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D011720:Pyrazoles; D000469:Alkaline Phosphatase