Synthesis and activity of a metabolite of (S)-6-amino-5-(6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamido)-3-methyl-1-phenyl-2,4-(1H,3H)-pyrimidinedione (CX-659S).
CX-659S (1) [(S)-6-amino-5-(6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamido)-3-methyl-1-phenyl-2,4-(1H,3H)-pyrimidinedione], has been developed as a new type anti-inflammatory agent for the treatment of dermatitis. The structure of a major metabolite of CX-659S was determined as (S)-6-amino-5-[2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadienyl)butanamide]-3-methyl-1-phenyl-2,4-(1H,3H)-pyrimidinedione (2) by direct comparison with the synthesized authentic compound. The anti-inflammatory activity of 2 was equipotent with that of 1 on the contact hypersensitivity reaction (CHR) induced by picryl chloride (PC) in mice, suggesting that compound 2 contributes, at least in part, to the anti-inflammatory activity of CX-659S.
Isobe
Yoshiaki
Y
Pharmaceuticals and Biotechnology Laboratory, Japan Energy Corporation, Toda, Saitama, Japan.
Tobe
Masanori
M
Takahashi
Osamu
O
Goto
Yuso
Y
Inoue
Yoshifumi
Y
Obara
Fumihiro
F
Tsuchiya
Masami
M
Hayashi
Hideya
H
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D003877:Dermatitis, Contact / Q000188:drug therapy; D004285:Dogs; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D014498:Uracil; C418807:CX 659S