749917-25-7Relevant academic research and scientific papers
Potent multitarget FAAH-COX inhibitors: Design and structure-activity relationship studies
Migliore, Marco,Habrant, Damien,Sasso, Oscar,Albani, Clara,Bertozzi, Sine Mandrup,Armirotti, Andrea,Piomelli, Daniele,Scarpelli, Rita
supporting information, p. 216 - 237 (2016/01/16)
Non-steroidal anti-inflammatory drugs (NSAIDs) exert their pharmacological effects by inhibiting cyclooxygenase (COX)-1 and COX-2. Though widely prescribed for pain and inflammation, these agents have limited utility in chronic diseases due to serious mechanism-based adverse events such as gastrointestinal damage. Concomitant blockade of fatty acid amide hydrolase (FAAH) enhances the therapeutic effects of the NSAIDs while attenuating their propensity to cause gastrointestinal injury. This favorable interaction is attributed to the accumulation of protective FAAH substrates, such as the endocannabinoid anandamide, and suggests that agents simultaneously targeting COX and FAAH might provide an innovative strategy to combat pain and inflammation with reduced side effects. Here, we describe the rational design and structure-active relationship (SAR) properties of the first class of potent multitarget FAAH-COX inhibitors. A focused SAR exploration around the prototype 10r (ARN2508) led to the identification of achiral (18b) as well as racemic (29a-c and 29e) analogs. Absolute configurational assignment and pharmacological evaluation of single enantiomers of 10r are also presented. (S)-(+)-10r is the first highly potent and selective chiral inhibitor of FAAH-COX with marked in vivo activity, and represents a promising lead to discover novel analgesics and anti-inflammatory drugs.
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.
