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 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.
Graduate School of Biomedical Sciences, Hiroshima University, Minami-ku, Hiroshima 734-8553, Japan.
Naoto
N
Uramaru
Hidenari
H
Shigematsu
Akihisa
A
Toda
Reiko
R
Eyanagi
Shigeyuki
S
Kitamura
Shigeru
S
Ohta
D000485:Allergens / Q000276:immunology*; D000700:Analgesics / Q000138:chemical synthesis* / Q000276:immunology / Q000494:pharmacology; D000818:Animals; D058633:Antipyretics / Q000138:chemical synthesis* / Q000276:immunology / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D015195:Drug Design; D005334:Fever / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D006168:Guinea Pigs; D006930:Hyperalgesia / Q000188:drug therapy / Q000276:immunology; D006968:Hypersensitivity, Delayed / Q000276:immunology; D066298:In Vitro Techniques; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D047069:Pyrazolones / Q000138:chemical synthesis* / Q000276:immunology / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012882:Skin Tests; D013329:Structure-Activity Relationship
D000485:Allergens; D000700:Analgesics; D058633:Antipyretics; D053583:Interleukin-1beta; D047069:Pyrazolones