title: Novel inhibitors of prolyl 4-hydroxylase. 3. Inhibition by the substrate analogue N-oxaloglycine and its derivatives.
abstract: N-Oxaloglycine (3) is an alpha-ketoglutarate (1) analogue that is a competitive inhibitor of prolyl 4-hydroxylase (EC 1.14.11.2). A study of the structure-activity relationships of some other oxalo derivatives shows that substitution on the glycine moiety modulates activity stereoselectively and that if the omega-carboxylate is homologated or replaced by either acylsulfonamides or anilide, then activity is sharply reduced. This sensitivity to these changes is contrasted with the relative insensitivity of another putative alpha-ketoglutarate analogue, pyridine-2,5-dicarboxylic acid (2), and the implication is discussed that compounds of both series are unlikely to bind to prolyl hydroxylase in the same way even though both inhibit the enzyme competitively.
authors.affiliation: Research Department I, ICI Pharmaceuticals, Macclesfield, Cheshire, United Kingdom.
authors.forename: C J
authors.initials: CJ
authors.lastname: Cunliffe
authors.forename: T J
authors.initials: TJ
authors.lastname: Franklin
authors.forename: N J
authors.initials: NJ
authors.lastname: Hales
authors.forename: G B
authors.initials: GB
authors.lastname: Hill
mesh_terms: D000595:Amino Acid Sequence; D000600:Amino Acids, Dicarboxylic / Q000138:chemical synthesis / Q000494:pharmacology*; D001667:Binding, Competitive; D008969:Molecular Sequence Data; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000600:Amino Acids, Dicarboxylic; D011393:Procollagen-Proline Dioxygenase; C040947:oxalylglycine