Journal of Medicinal Chemistry 1993-11-26

Novel inhibitors of prolyl 4-hydroxylase. 5. The intriguing structure-activity relationships seen with 2,2'-bipyridine and its 5,5'-dicarboxylic acid derivatives.

N J Hales, J F Beattie

Index: J. Med. Chem. 36(24) , 3853-8, (1993)

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Abstract

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 microM) 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.