Phosphatase inhibitors--III. Benzylaminophosphonic acids as potent inhibitors of human prostatic acid phosphatase.
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.
Beers
S A
SA
R.W. Johnson Pharmaceutical Research Institute, Raritan NJ 08869, USA.
Schwender
C F
CF
Loughney
D A
DA
Malloy
E
E
Demarest
K
K
Jordan
J
J
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
D001592:Benzyl Alcohols; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D000135:Acid Phosphatase