Design, Synthesis, and Pharmacological Activity of Nonallergenic Pyrazolone-Type Antipyretic Analgesics

To develop novel nonallergenic pyrazolone analgesics, we synthesized a series of compounds in which position 1 of the pyrazolone ring was substituted in place of the original methyl group in order to block the formation of allergenic metabolites via N-dealkylation. These pyrazolone analogues were fo...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2010-12, Vol.53 (24), p.8727-8733
Main Authors: Uramaru, Naoto, Shigematsu, Hidenari, Toda, Akihisa, Eyanagi, Reiko, Kitamura, Shigeyuki, Ohta, Shigeru
Format: Article
Language:English
Subjects:
Allergens - immunology
Analgesics - chemical synthesis
Analgesics - immunology
Analgesics - pharmacology
Animals
Antipyretics - chemical synthesis
Antipyretics - immunology
Antipyretics - pharmacology
Body Temperature - drug effects
Drug Design
Fever - drug therapy
Fever - immunology
Fever - physiopathology
Guinea Pigs
Hyperalgesia - drug therapy
Hyperalgesia - immunology
Hypersensitivity, Delayed - immunology
In Vitro Techniques
Interleukin-1beta - pharmacology
Male
Microsomes, Liver - metabolism
Pyrazolones - chemical synthesis
Pyrazolones - immunology
Pyrazolones - pharmacology
Rats
Rats, Sprague-Dawley
Skin Tests
Structure-Activity Relationship
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Summary:To develop novel nonallergenic pyrazolone analgesics, we synthesized a series of compounds in which position 1 of the pyrazolone ring was substituted in place of the original methyl group in order to block the formation of allergenic metabolites via N-dealkylation. These pyrazolone analogues were found to show as potent an antipyretic and analgesic effect as antipyrine (AT). In an examination of allergenicity, AT induced a typical skin reaction in guinea pigs, whereas the pyrazolone analogues were inactive. When AT was administered (po) to rats, norantipyrine (NORA) as an active metabolite was detected in the urine, whereas similar administration of the pyrazolone analogues did not afford NORA. We conclude that these novel pyrazolone analogues were nonallergenic because they were not converted to allergenic metabolites in vivo. Because these compounds retain the antipyretic and analgesic activities of AT, they are considered to be promising candidates for nonallergenic antipyretic analgesics.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm101208x