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An extensive series of novel 4-substituted 3-hydroxy-1H-pyrrole-2,5-dione derivatives has been prepared and studied as inhibitors of glycolic acid oxidase (GAO). Compounds possessing large lipophilic 4-substituents are, in general, potent, competitive inhibitors of porcine liver GAO in vitro. Methylation of the nitrogen or the 3-hydroxy substituent reduced potency dramatically, indicating the requirement for the two acidic functions on the 1H-pyrrole-2,5-dione nucleus. In rat liver perfusion studies, with three representative compounds, concentration-dependent inhibition of the conversion of [1-14C]glycolate to [14C]oxalate was observed. Chronic oral administration to ethylene glycol fed rats of the 4-(4'-bromo[1,1'-biphenyl]-4-yl) derivative (83) was shown to effect a significant reduction in urinary oxalate levels over a 58-day period.
C S Rooney, and
W C Randall, and
K B Streeter, and
C Ziegler, and
E J Cragoe, and
H Schwam, and
S R Michelson, and
H W Williams, and
E Eichler, and
D E Duggan, and
E H Ulm, and
R M Noll
January 2010,
Bioorganic & medicinal chemistry letters,
C S Rooney, and
W C Randall, and
K B Streeter, and
C Ziegler, and
E J Cragoe, and
H Schwam, and
S R Michelson, and
H W Williams, and
E Eichler, and
D E Duggan, and
E H Ulm, and
R M Noll
April 2007,
Acta crystallographica. Section C, Crystal structure communications,
C S Rooney, and
W C Randall, and
K B Streeter, and
C Ziegler, and
E J Cragoe, and
H Schwam, and
S R Michelson, and
H W Williams, and
E Eichler, and
D E Duggan, and
E H Ulm, and
R M Noll
May 2012,
Acta crystallographica. Section E, Structure reports online,
C S Rooney, and
W C Randall, and
K B Streeter, and
C Ziegler, and
E J Cragoe, and
H Schwam, and
S R Michelson, and
H W Williams, and
E Eichler, and
D E Duggan, and
E H Ulm, and
R M Noll
March 2012,
Bioorganic & medicinal chemistry letters,
C S Rooney, and
W C Randall, and
K B Streeter, and
C Ziegler, and
E J Cragoe, and
H Schwam, and
S R Michelson, and
H W Williams, and
E Eichler, and
D E Duggan, and
E H Ulm, and
R M Noll
January 2017,
Anti-cancer agents in medicinal chemistry,
C S Rooney, and
W C Randall, and
K B Streeter, and
C Ziegler, and
E J Cragoe, and
H Schwam, and
S R Michelson, and
H W Williams, and
E Eichler, and
D E Duggan, and
E H Ulm, and
R M Noll
June 2013,
Acta crystallographica. Section E, Structure reports online,
C S Rooney, and
W C Randall, and
K B Streeter, and
C Ziegler, and
E J Cragoe, and
H Schwam, and
S R Michelson, and
H W Williams, and
E Eichler, and
D E Duggan, and
E H Ulm, and
R M Noll
April 2011,
Acta crystallographica. Section E, Structure reports online,
C S Rooney, and
W C Randall, and
K B Streeter, and
C Ziegler, and
E J Cragoe, and
H Schwam, and
S R Michelson, and
H W Williams, and
E Eichler, and
D E Duggan, and
E H Ulm, and
R M Noll
July 2012,
Acta crystallographica. Section E, Structure reports online,
C S Rooney, and
W C Randall, and
K B Streeter, and
C Ziegler, and
E J Cragoe, and
H Schwam, and
S R Michelson, and
H W Williams, and
E Eichler, and
D E Duggan, and
E H Ulm, and
R M Noll
February 2017,
Chemistry & biodiversity,
C S Rooney, and
W C Randall, and
K B Streeter, and
C Ziegler, and
E J Cragoe, and
H Schwam, and
S R Michelson, and
H W Williams, and
E Eichler, and
D E Duggan, and
E H Ulm, and
R M Noll
September 2011,
Acta crystallographica. Section E, Structure reports online,
