Novel inhibitors of prolyl 4-hydroxylase.
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.
Dowell
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Chemistry 1 Department, ICI Pharmaceuticals, Macclesfield, Cheshire, United Kingdom.
Hadley
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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*
D011725:Pyridines; D013449:Sulfonamides; C043093:2,5-Pyridinedicarboxylic acid; D011393:Procollagen-Proline Dioxygenase