Design, synthesis, and in-vivo evaluation of 4,5-diaryloxazole as novel nonsteroidal anti-inflammatory drug.
A series of 4,5-diaryloxazole analogs were designed and the interaction between oxaprozin and cyclooxygenase-2 studied by the docking method to improve the biological activity and reduce the gastrointestinal side effects of oxaprozin. Finally, 3-(4-(4-fluorophenyl)-5-(4-aminosulfonyl-3-fluorophenyl)-oxazole-2-yl) propanoic acid (NC-2142), the best candidate, was selected for synthesis and bioassay based on the screening result. NC-2142 could lower the tumefaction rates of back metatarsus in rats, as well as reduce the writhing times in mice. NC-2142 produced fewer gastric lesions than oxaprozin. After the aminosulfonyl group was introduced into the benzene ring of oxaprozin, its analgesic and anti-inflammatory activities remained unchanged, and it reduced the number of gastric lesions. This provided a feasible method for further structure modification and optimization of oxaprozin.
Zhou
Xiao-ping
XP
Department of Medicinal Chemistry, School of Pharmacy, Jilin University, China.
Zhang
Mu-xin
MX
Sun
Wei
W
Yang
Xiao-hong
XH
Wang
Guang-shu
GS
Sui
Da-yuan
DY
Yu
Xiao-feng
XF
Qu
Shao-chun
SC
D000700:Analgesics / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D051546:Cyclooxygenase 2 / Q000737:chemistry; D004487:Edema / Q000188:drug therapy*; D005260:Female; D008297:Male; D008682:Metatarsal Bones / Q000187:drug effects / Q000503:physiopathology; D051379:Mice; D008815:Mice, Inbred Strains; D000077431:Oxaprozin; D010146:Pain / Q000188:drug therapy*; D011422:Propionates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013270:Stomach / Q000187:drug effects* / Q000473:pathology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*
C548357:3-(4-(4-fluorophenyl)-5-(4-aminosulfonyl-3-fluorophenyl)oxazole-2-yl)propanoic acid; D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011422:Propionates; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D000077431:Oxaprozin