Properties and synthesis of 2-{2-fluoro (or bromo)-4-[(2-oxocyclopentyl)methyl]phenyl}propanoic acid: nonsteroidal anti-inflammatory drugs with low membrane permeabilizing and gastric lesion-producing activities.
We previously proposed that membrane permeabilization activity of NSAIDs is involved in NSAID-induced gastric lesions. We here synthesized derivatives of loxoprofen that have lower membrane permeabilization activity than other NSAIDs. Compared to loxoprofen, the derivatives 10a and 10b have lower membrane permeabilization activity and their oral administration produced fewer gastric lesions but showed an equivalent anti-inflammatory effect. These results suggest that 10a and 10b are likely to be therapeutically beneficial as safer NSAIDs.
Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
Naoki
N
Yamakawa
Shintaro
S
Suemasu
Masaaki
M
Matoyama
Ayumi
A
Kimoto
Miho
M
Takeda
Ken-Ichiro
K
Tanaka
Tomoaki
T
Ishihara
Takashi
T
Katsu
Yoshinari
Y
Okamoto
Masami
M
Otsuka
Tohru
T
Mizushima
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry; D002463:Cell Membrane Permeability; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology; D005753:Gastric Mucosa / Q000187:drug effects* / Q000473:pathology; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced / Q000473:pathology; D006801:Humans; D010666:Phenylpropionates / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D011355:Prodrugs / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D010666:Phenylpropionates; D011355:Prodrugs; C040656:loxoprofen