title: Design and synthesis of pyrazole derivatives as potent and selective inhibitors of tissue-nonspecific alkaline phosphatase (TNAP).
abstract: 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.
authors.affiliation: Burnham Center for Chemical Genomics, Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
authors.forename: Shyama
authors.initials: S
authors.lastname: Sidique
authors.forename: Robert
authors.initials: R
authors.lastname: Ardecky
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.forename: Sonoko
authors.initials: S
authors.lastname: Narisawa
authors.forename: Brock
authors.initials: B
authors.lastname: Brown
authors.forename: José Luis
authors.initials: JL
authors.lastname: Millán
authors.forename: Eduard
authors.initials: E
authors.lastname: Sergienko
authors.forename: Nicholas D P
authors.initials: ND
authors.lastname: Cosford
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D011720:Pyrazoles; D000469:Alkaline Phosphatase