Synthesis and evaluation of novel purple acid phosphatase inhibitors.

Transgenic studies in animals have demonstrated a direct association between the level of expression of purple acid phosphatase (PAP; also known as tartrate-resistant acid phosphatase) and the progression of osteoporosis. Consequently, PAP has emerged as a promising target for the development of novel therapeutic agents to treat this debilitating disorder. PAPs are binuclear hydrolases that catalyse the hydrolysis of phosphorylated substrates under acidic to neutral conditions. A series of phenyltriazole carboxylic acids, prepared by the reactions of azide derivatives with propiolic acid through copper(i)-catalysed azide-alkyne cycloaddition click reactions, has been assessed for their inhibitory effect on the catalytic activity of pig and red kidney bean PAPs. The binding mode of most of these compounds is purely uncompetitive with K_iuc values as low as ∼23 μM for the mammalian enzyme. Molecular modelling has been used to examine the binding modes of these triazole compounds in the presence of a substrate in the active site of the enzyme in order to rationalise their activities and to design more potent and specific derivatives.