Prodrugs isoxazole

Of interest here is that certain drugs and prodrugs that contain an isoxazole ring are metabolized to a cyano enol, e.g., leflunomide (11.122, R = CF3, R = H), a prodrug of the potential anti-arthritic agent 2-cyano-3-hydroxy-A-[4-(trifluoromethyl)phenyl]but-2-enamide (11.123). After oral administration of 50 mg/kg of 11.122 to rats, the plasma concentration of the prodrug peaked at 1 pg/ml and dropped rapidly, whereas the concentration of the active metabolite 11.123 was maintained at ca. 100 pg/ml for 24 h [147]. This... 

The prodrug leflunomide (A-(4 -trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide) is an isoxazole derivative. Its main metabolite is the active compound, A77 1726 (1). 

Leflunomide (Arava) is an anti-proliferative drug that inhibits dihydroorotate dehydrogenase, an enzyme essential for the synthesis of pyrimidines such as uracil, via aromatisation of dihydroorotic acid. It also has some immunomodulatory effects and is useful for intractable cases of rheumatoid arthritis, despite being liable to cause a number of serious side-effects. It is actually a prodrug, being converted into the active compound, a nitrile formed by cleavage of the isoxazole ring (cf. 25.5.1). 

As already mentioned, isoxazoles such as I FT are prodrugs and are not sufficiently persistent in plants to inhibit the HP PD enzyme. It is the first metabolite of isoxaflutole, the so-called DKN (diketonitrile) 3-cyclopropyl-2-[2-(methylsulfonyl)-4-(trifluoromethyl)benzoyl]-3-oxopropanenitrile (25) that is the herbicidally active entity. In soil, and also in plants, I FT undergoes rapid conversion into DKN [25]. In aqueous solutions there is an influence of temperature and pH on the chemical hydrolysis of IFT to DKN. The hydrolysis increases with increasing pH and temperature for 295 K and pH 9.3 the rate of degradation was 100-fold faster than at pH 3.8. (Scheme 4.4.7) [26]. The DT50 in water is 11 days at pH 5, 20 h at pH 7 and 3 h at pH 9 [22]. 

Tilmacoxib is a COX-2 inhibiting, oxazole-containing, nonsteroidal anti-inflammatory agent, and valdecoxib is an isoxazole NSAID. Formation of the sodium salt of an A -acylated derivative of valdecoxib affords parecoxib, a water-soluble valdecoxib prodrug amenable to injectable formulations. Valdecoxib was withdrawn from the US market in 2005 due to concern of increased risk of heart attack or stroke. While parecoxib is approved for use in the EU, the US FDA issued a letter of nonapproval for the drug, also in 2005. While no documentation for the nonapproval was made public, proximity to the 2004 withdrawal of rofecoxib (Vioxx) cannot be overlooked. 

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