title: Novel inhibitors of prolyl 4-hydroxylase.
abstract: A series of 5-acyl sulfonamides derived from pyridine-2,5-dicarboxylic acid (15) has been prepared and several members of this series have been shown to be more potent, in vitro, as inhibitors of prolyl 4-hydroxylase than 15. Several chain-extended pyridinedicarboxylic acids have also been prepared and shown to be potent inhibitors of prolyl 4-hydroxylase. The structure-activity in both these series is discussed. The results indicate that the 5-carboxylic acid binding site, in the enzyme, can accept a carboxylic acid or an acyl sulfonamide equally well. This indicates a much greater degree of freedom in this distal carboxylic acid binding site than is predicted by the current theoretical model of the active site.
authors.affiliation: Chemistry 1 Department, ICI Pharmaceuticals, Macclesfield, Cheshire, United Kingdom.
authors.forename: R I
authors.initials: RI
authors.lastname: Dowell
authors.forename: E M
authors.initials: EM
authors.lastname: Hadley
mesh_terms: D001665:Binding Sites; D015394:Molecular Structure; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D011725:Pyridines; D013449:Sulfonamides; C043093:2,5-Pyridinedicarboxylic acid; D011393:Procollagen-Proline Dioxygenase