NOVEL INHIBITORS OF PROLYL 4-HYDROXYLASE .5. THE INTRIGUING STRUCTURE-ACTIVITY-RELATIONSHIPS SEEN WITH 2,2'-BIPYRIDINE AND ITS 5,5'-DICARBOXYLIC ACID-DERIVATIVES

Members of a series of 2,2'-bipyridines have been synthesized and tested as inhibitors of prolyl hydroxylase (EC 1.14.11.2). The structure-activity relationships seen with [2,2'-bipyridine]-5-carboxylic acid (4) closely resemble those of pyridine-2-carboxylic acid (2). Accordingly, [2,2'-bipyridine]-5,5'-dicarboxylic acid (11, IC50 = 0.19 mu M) is the most potent inhibitor of its type yet reported. However, 2,2'-bipyridines lacking a 5-carboxylate are poor inhibitors. These contrasting structure-activity relationships are discussed in terms of net anionic charge, iron chelation, and the availability of alternative putative binding modes at a single binding site in each catalytic subunit.