Synthesis and enzymic activity of some novel xanthine oxidase inhibitors. 3-Substituted 5,7-dihydroxypyrazolo(1,5-alpha)pyrimidines.

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Springer RH, Dimmitt MK, Novinson T, O'Brien DE, Robins RK, Simon LN, Miller JP

Synthesis and enzymic activity of some novel xanthine oxidase inhibitors. 3-Substituted 5,7-dihydroxypyrazolo(1,5-alpha)pyrimidines.

J Med Chem. 1976 Feb;19(2):291-6.

PubMed ID

2778 [ View in PubMed

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Abstract

A series of 3-substituted 5,7-dihydroxypyrazolo[1,5-alpha]pyrimidines containing various aromatic [phenyl- (3e), 3-pyridyl- (3f), p-bromophenyl- (3g), p-chlorophenyl- (3h), p-acetamidophenyl- (3i), p-tolyl- (3j), m-tolyl- (3k), 3,4-methylenedioxyphenyl- (3m), or naphthyl- (3n)] or nonaromatic [hydrogen- (3a), nitro- (3b), bromo- (3c), or chloro- (3d)] substituents in the 3 position was synthesized and tested as inhibitors of xanthine oxidase. The compounds (3a-m) were synthesized by condensation of the appropriate 3-amino-4-substituted pyrazole with diethyl malonate in alcoholic sodium methoxide and neutralization of the resulting enol sodium salts. As inhibitors of xanthine oxidase, 3e-n greater than 3a,c,d congruent to allopurinol greater than 3b. The 3-aryl-substituted compounds 3e-n were 30-160 times better xanthine oxidase inhibitors than allopurinol using hypoxanthine as substrate and 10-80 times better using xanthine as substrate, as evidenced by a comparison of Ki values. The inhibition by all compounds (3a-n) was totally reversible and of the noncompetitive or mixed type. A study of the pH dependence of xanthine oxidase inhibition by 3a,e,g and allopurinol indicated that the 3-aryl substituents facilitated binding to the enzyme. These and the above results show that the compounds reported here inhibit xanthine oxidase by a mechanism which is significantly different from that of allopurinol.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Chlorphenesin	Xanthine dehydrogenase/oxidase	Protein	Humans	Unknown	Inhibitor	Details