title: Phosphatase inhibitors--III. Benzylaminophosphonic acids as potent inhibitors of human prostatic acid phosphatase.
abstract: Further investigation of the structural requirements of a series of benzylphosphonic acid inhibitors of human prostatic acid phosphatase has led to the highly potent series of alpha-aminobenzylphosphonic acids. The alpha-benzylaminobenzylphosphonic acid, with an IC50 = 4 nM, exhibited a 3500-fold improvement in potency over the carbon analogue, alpha-phenylethyl. The enhanced potency may be due to a combination of four favorable interactions including those with the phosphate binding region, the presence the hydrophobic moieties of the benzylamino and phenylphosphonic acid, and a rigid conformer produced by an internal salt bridge between the phosphonate and the alpha-amino group. Replacement of the phosphonic acid moiety with a phosphinic or carboxylic acid as well as deletion of the benzyl substitution of the alpha-amino group led to great reductions in potency.
authors.affiliation: R.W. Johnson Pharmaceutical Research Institute, Raritan NJ 08869, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Beers
authors.forename: C F
authors.initials: CF
authors.lastname: Schwender
authors.forename: D A
authors.initials: DA
authors.lastname: Loughney
authors.forename: E
authors.initials: E
authors.lastname: Malloy
authors.forename: K
authors.initials: K
authors.lastname: Demarest
authors.forename: J
authors.initials: J
authors.lastname: Jordan
mesh_terms: D000135:Acid Phosphatase / Q000037:antagonists & inhibitors*; D001592:Benzyl Alcohols; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D008297:Male; D008958:Models, Molecular; D063065:Organophosphonates / Q000737:chemistry*; D011467:Prostate / Q000201:enzymology*; D011487:Protein Conformation
chemical_list: D001592:Benzyl Alcohols; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D000135:Acid Phosphatase