title: Synthesis, modelling and kinetic assays of potent inhibitors of purple acid phosphatase.
abstract: Purple acid phosphatases (PAPs) are binuclear metallohydrolases that have been isolated from various mammals, plants, fungi and bacteria. In mammals PAP activity is associated with bone resorption and can lead to bone metabolic disorders such as osteoporosis; thus human PAP is an attractive target to develop anti-osteoporotic drugs. Based on a previous lead compound and rational drug design, acyl derivatives of α-aminonaphthylmethylphosphonic acid were synthesised and tested as PAP inhibitors. Kinetic analysis showed that they are good PAP inhibitors whose potencies improve with increasing acyl chain length. Maximum potency is reached when the number of carbons in the acyl chain is between 12 and 14. The most potent inhibitor of red kidney bean PAP is the dodecyl-derivative with K(ic)=5 μM, while the most potent pig PAP inhibitor is the tetradecyl-derivative with K(ic)=8 μM, the most potent inhibitor of a mammalian PAP yet reported.
authors: The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, Qld 4072, Australia.
authors: Siti Hajar
authors: SH
authors: Mohd-Pahmi
authors: Waleed M
authors: WM
authors: Hussein
authors: Gerhard
authors: G
authors: Schenk
authors: Ross P
authors: RP
authors: McGeary
mesh_terms: D000135:Acid Phosphatase / Q000037:antagonists & inhibitors*; D000818:Animals; D001667:Binding, Competitive; D001681:Biological Assay; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D015394:Molecular Structure; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D010944:Plants / Q000201:enzymology; D013552:Swine
chemical_list: D004791:Enzyme Inhibitors; D006023:Glycoproteins; D063065:Organophosphonates; C091137:purple acid phosphatase; D000135:Acid Phosphatase