- HR1405-01, a Safe intravenous NSAID with superior anti-inflammatory and analgesic activities in preclinical trials
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Combinational utilization of intravenous non-steroidal anti-inflammatory drugs (NSAIDs) with opium analgesic is an effective alternative modality for pain control after surgery. This regimen is known for reducing the risk of addiction induced by opium analgesic. However, current intravenous NSAIDs have solubility problems, limiting their clinical applications. Although loxoprofen exhibits strong anti-inflammatory and analgesic activities with relatively low ulcerogenicity, its relatively low bioavailability makes it not an ideal drug candidate for intravenous injection. We selected the bioactive metabolite (6) of loxoprofen as a candidate and developed a new intravenous NSAID, HR1405–01. This metabolite exhibited significantly stronger anti-inflammatory and analgesic activities than parecoxib sodium injection or ibuprofen injection. The excellent potency and solubility of HR1405–01 allowed the avoidance of utilization of cosolvent in the formulation, resulting in fewer side effects and a better safety profile. Therefore, HR1405–01 might be a promising candidate for the development of a new intravenous NSAID.
- Chen, Xingran,Ding, Boxiang,Lv, Tian,Mao, Di,Min, Tao,Ye, Hai,Zhang, Can
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- 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
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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.
- Yamakawa, Naoki,Suemasu, Shintaro,Matoyama, Masaaki,Kimoto, Ayumi,Takeda, Miho,Tanaka, Ken-Ichiro,Ishihara, Tomoaki,Katsu, Takashi,Okamoto, Yoshinari,Otsuka, Masami,Mizushima, Tohru
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scheme or table
p. 7879 - 7882
(2011/02/22)
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- Evaluation of loxoprofen and its alcohol metabolites for potency and selectivity of inhibition of cyclooxygenase-2
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Loxoprofen, its trans-alcohol and cis-alcohol metabolites were evaluated for selectivity of inhibition of COX-2 over COX-1. The (2S,1′R,2′S)- trans-alcohol derivative was found to be the most active metabolite and to be a potent and nonselective inhibitor of COX-2 and COX-1 in both enzyme and human whole blood assays.
- Riendeau, Denis,Salem, Myriam,Styhler, Angela,Ouellet, Marc,Mancini, Joseph A.,Li, Chun Sing
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p. 1201 - 1203
(2007/10/03)
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- Reduction of drug ketones by dihydrodiol dehydrogenases, carbonyl reductase and aldehyde reductase of human liver
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In this study, we compared the enzymatic reduction of 10 drugs with a ketone group by homogeneous carbonyl reductase, aldehyde reductase and three dihydrodiol dehydrogenases of human liver cytosol. At least one and in some cases all of the three dihydrodi
- Ohara, Hirotami,Miyabe, Yoshiyuki,Deyashiki, Yoshihiro,Matsuura, Kazuya,Hara, Akira
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p. 221 - 227
(2007/10/03)
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- Synthesis of the eight possible optically active isomers of 2-[4-(2-hydroxycyclopentylmethyl)phenyl]propionic acid
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A recently synthesized compound, (±)-2-[4-(2-oxocyclopentylmethyl)phenyl]propionic acid, had good anti-inflammatory and analgesic activities. One of the metabolites of this compound showed more potent prostaglandin synthetase inhibitory activity than the
- Naruto,Terada
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p. 4319 - 4323
(2007/10/02)
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