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 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.
Hales
N J
NJ
Infection Research Department, Zeneca Pharmaceuticals, Macclesfield, Cheshire, United Kingdom.
Beattie
J F
JF
D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D015394:Molecular Structure; D009539:Nicotinic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D009539:Nicotinic Acids; C084675:(2,2'-bipyridine)-5,5'-dicarboxylic acid; C084674:(2,2'-bipyridine)-5-carboxylic acid; D015082:2,2'-Dipyridyl; D011393:Procollagen-Proline Dioxygenase