52807-12-2Relevant articles and documents
CYP2C9 genotype-dependent effects on in vitro drug-drug interactions: Switching of benzbromarone effect from inhibition to activation in the CYP2C9.3 variant
Hummel, Matthew A.,Locuson, Charles W.,Gannett, Peter M.,Rock, Dan A.,Mosher, Carrie M.,Rettie, Allan E.,Tracy, Timothy S.
, p. 644 - 651 (2005)
The CYP2C9.3 variant exhibits marked decreases in substrate turnover compared with the wild-type enzyme, but little is known regarding the effect this variant form may have on the occurrence of drug-drug interactions. To examine this possibility, the effect of the potent CYP2C9 inhibitor, benzbromarone, was studied with regard to CYP2C9.1- and CYP2C9.3-mediated flurbiprofen metabolism to evaluate whether the variant enzyme exhibits differential inhibition kinetics. Although benzbromarone inhibited CYP2C9.1 activity as expected, CYP2C9.3-mediated flurbiprofen 4′-hydroxylation was activated in the presence of benzbromarone. T1 relaxation studies revealed little change in distances of flurbiprofen protons from the heme iron of either CYP2C9.1 or CYP2C9.3 in the presence of benzbromarone compared with flurbiprofen alone. Spectral binding studies were also performed to investigate whether benzbromarone affected substrate binding, with the addition of benzbromarone having little effect on flurbiprofen-binding affinity in both CYP2C9.1 and CYP2C9.3. Docking studies with the 2C9.1 structure crystallized with a closed active site identified multiple but overlapping subsites with sufficient space for benzbromarone binding in the enzyme when flurbiprofen was positioned closest to the heme. If the closed conformation of 2C9.3 is structurally similar to 2C9.1, as expected for the conservative I359L mutation, then the dynamics of benzbromarone binding may account for the switching of drug interaction effects. In conclusion, the I359L amino acid substitution found in CYP2C9.3 not only reduces metabolism compared with CYP2C9.1 but can also dramatically alter inhibitor effects, suggesting that differential degrees of drug inhibition interactions may occur in individuals with this variant form of CYP2C9. Copyright
NO-donating tacrine derivatives as potential butyrylcholinesterase inhibitors with vasorelaxation activity
Chen, Yao,Sun, Jianfei,Huang, Zhangjian,Liao, Hong,Peng, Sixun,Lehmann, Jochen,Zhang, Yihua
, p. 3162 - 3165 (2013/06/27)
To search for potent anti-Alzheimer's disease (AD) agents with multifunctional effects, 12 NO-donating tacrine-flurbiprofen hybrid compounds (2a-l) were synthesized and biologically evaluated. It was found that all the new target compounds showed selective butyrylcholinesterase (BuChE) inhibitory activity in vitro comparable or higher than tacrine and the tacrine-flurbiprofen hybrid compounds 1a-c, and released moderate amount of NO in vitro. The kinetic study suggests that one of the most active and highest BuChE selective compounds 2d may not only compete with the substrate for the same catalytic active site (CAS) but also interact with a second binding site. Furthermore, 2d and 2l exhibited significant vascular relaxation effect, which is beneficial for the treatment of AD. All the results suggest that 2d and 2l might be promising lead compounds for further research.
Synthesis and biological activity of flurbiprofen analogues as selective inhibitors of β-amyloid1-42 secretion
Peretto, Ilaria,Radaelli, Stefano,Parini, Carlo,Zandi, Michele,Raveglia, Luca F.,Dondio, Giulio,Fontanella, Laura,Misiano, Paola,Bigogno, Chiara,Rizzi, Andrea,Riccardi, Benedetta,Biscaioli, Marcello,Marchetti, Silvia,Puccini, Paola,Catinella, Silvia,Rondelli, Ivano,Cenacchi, Valentina,Bolzoni, Pier Tonino,Caruso, Paola,Villetti, Gino,Facchinetti, Fabrizio,Del Giudice, Elda,Moretto, Nadia,Imbimbo, Bruno P.
, p. 5705 - 5720 (2007/10/03)
Flurbiprofen, a nonsteroidal antiinflammatory drug (NSAID), has been recently described to selectively inhibit β-amyloid1-42 (Aβ42) secretion, the most toxic component of the senile plaques present in the brain of Alzheimer patients. The use of this NSAID in Alzheimer's disease (AD) is hampered by a significant gastrointestinal toxicity associated with cyclooxygenase (COX) inhibition. New flurbiprofen analogues were synthesized, with the aim of increasing Aβ42 inhibitory potency while removing anti-COX activity. In vitro ADME developability parameters were taken into account in order to identify optimized compounds at an early stage of the project. Appropriate substitution patterns at the alpha position of flurbiprofen allowed for the complete removal of anti-COX activity, while modifications at the terminal phenyl ring resulted in increased inhibitory potency on Aβ42 secretion. In rats, some of the compounds appeared to be well absorbed after oral administration and to penetrate into the central nervous system. Studies in a transgenic mice model of AD showed that selected compounds significantly decreased plasma Aβ42 concentrations. These new flurbiprofen analogues represent potential drug candidates to be developed for the treatment of AD.
