Pyrazolopyrimidine metabolism

Matt JJ. Pyrazolopyrimidine metabolism in Leishmania and trypanosomes Significant difierences between host and parasite. J Cell Biochem 1983 22(3) 187-196. 

Ullman B. Pyrazolopyrimidine metabolism in parasitic protozoa. Pharmaceutical Research 1984 l(5) 194-203. 

Figure Comparison of purine and pyrazolopyrimidine metabolism in Leishmania...

This newest non-BZD hypnotic is a pyrazolopyrimidine derivative with a fuii agonist activity on centrai BZD receptors B2 type. It is an effective hypnotic for the short-term treatment of insomnia. Because of its very short half-life (almost an hour), it may be useful for patients experiencing difficulty falling asleep and in those who wake up at night and who have trouble falling back to sleep. Zaleplon is rapidly absorbed after oral administration and its mean, apparent elimination half-life is similar to that obtained after i.v. infusion. Zaleplon is extensively metabolized in the liver by aldehyde oxidase, and to a lesser extent by CYP3A4. This drug is excreted in the urine (156). 

Zaleplon is a pyrazolopyrimidine, and like zolpidem it binds selectively to the benzodiazepine-1 receptor. Zaleplon has a rapid onset of action, a half-life of 1 hour, and is metabolized to inactive metabolites. It is effective for decreasing time to sleep onset, but not for reducing nighttime awakening or for increasing the total sleep time. Zaleplon may be best used as a sleep aid for middle-of-the-night awakenings. 

Pyrazolopyrimidines are purine analogues in which the nitrogen and carbon of the imidazole ring are inverted. The best known member of this group, allopurinol (4-hydroxypyrazolo(3,4-d)pyrimidine HPP), is a structural analogue of hypoxanthine. Its major metabolic conversions in mammalian cells are to oxipurinol, via xanthine oxidase, and to allopurinol ribonucleoside (HPPR)l. 

A review of the information obtained to this point in the investigation indicated there were several promising avenues for exploration the pyrazolopyrimidine structure was accepted by enzymes of purine metabolism in these organisms the pyrazolopyrimidine bases could be activated by the appropriate PRTases the ribonucleoside could be activated by another route the ribonucleoside was stable to nucleoside cleaving activities of these cells. Thus, both pyrazolopyrimidine bases and ribonucleosides could be tested. Many analogues were investigated for their activities... 

The left panel indicates normal purine salvage pathways. The panel on the right summarizes the metabolism of pyrazolopyrimidine analogues. The X in the 4 position indicates the possibility of substituting the following groups -OH, -SH, -NH2. The pyrazolopyrimidine abbreviations are given in the text. The enzymes which mediate the pyrazolopyrimidine conversions are those listed in the left panel. 

What is the mechanism of this drug induced interference with pyrimidine metabolism The finding of orotic acid and orotidine in the urine is similar to that seen after therapy with the drug 6-azauridine. This compound is converted by a pyrimidine kinase to 6-azauridylic acid which competitively inhibits ODC (Handschumacher, 1960). By analogy a nucleotide derivative of allopurinol, oxipurinol or a metabolite may be a competitive inhibitor of ODC. In addition, a purine or pyrazolopyrimidine base could act as an inhibitor of OPRT or both mechanisms could work in concert. Finally, depletion of an essential substrate such as PP-ribose-P could also contribute. 

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