Design, synthesis and in vitro and in vivo biological evaluation of flurbiprofen amides as new fatty acid amide hydrolase/cyclooxygenase-2 dual inhibitory potential analgesic agents

TY - JOUR

T1 - Design, synthesis and in vitro and in vivo biological evaluation of flurbiprofen amides as new fatty acid amide hydrolase/cyclooxygenase-2 dual inhibitory potential analgesic agents

AU - Deplano, Alessandro

AU - Karlsson, Jessica

AU - Moraca, Federica

AU - Svensson, Mona

AU - Cristiano, Claudia

AU - Morgillo, Carmine Marco

AU - Fowler, Christopher J.

AU - Russo, Roberto

AU - Catalanotti, Bruno

AU - Onnis, Valentina

N1 - CF would like to thank the Research Funds of the Medical Faculty, Umeå University, for financial support.

PY - 2021

Y1 - 2021

N2 - Compounds combining dual inhibitory action against FAAH and cyclooxygenase (COX) may be potentially useful analgesics. Here, we describe a novel flurbiprofen analogue, N-(3-bromopyridin-2-yl)-2-(2-fluoro-(1,1'-biphenyl)-4-yl)propanamide (Flu-AM4). The compound is a competitive, reversible inhibitor of FAAH with a Ki value of 13 nM and which inhibits COX activity in a substrate-selective manner. Molecular modelling suggested that Flu-AM4 optimally fits a hydrophobic pocket in the ACB region of FAAH, and binds to COX-2 similarly to flurbiprofen. In vivo studies indicated that at a dose of 10 mg/kg, Flu-AM4 was active in models of prolonged (formalin) and neuropathic (chronic constriction injury) pain and reduced the spinal expression of iNOS, COX-2, and NFκB in the neuropathic model. Thus, the present study identifies Flu-AM4 as a dual-action FAAH/substrate-selective COX inhibitor with anti-inflammatory and analgesic activity in animal pain models. These findings underscore the potential usefulness of such dual-action compounds.

AB - Compounds combining dual inhibitory action against FAAH and cyclooxygenase (COX) may be potentially useful analgesics. Here, we describe a novel flurbiprofen analogue, N-(3-bromopyridin-2-yl)-2-(2-fluoro-(1,1'-biphenyl)-4-yl)propanamide (Flu-AM4). The compound is a competitive, reversible inhibitor of FAAH with a Ki value of 13 nM and which inhibits COX activity in a substrate-selective manner. Molecular modelling suggested that Flu-AM4 optimally fits a hydrophobic pocket in the ACB region of FAAH, and binds to COX-2 similarly to flurbiprofen. In vivo studies indicated that at a dose of 10 mg/kg, Flu-AM4 was active in models of prolonged (formalin) and neuropathic (chronic constriction injury) pain and reduced the spinal expression of iNOS, COX-2, and NFκB in the neuropathic model. Thus, the present study identifies Flu-AM4 as a dual-action FAAH/substrate-selective COX inhibitor with anti-inflammatory and analgesic activity in animal pain models. These findings underscore the potential usefulness of such dual-action compounds.

KW - Flurbiprofen amides

KW - FAAH inhibition

KW - fatty acid amide hydrolase

KW - endocannabinoid

KW - cyclooxygenase

KW - non-steroidal anti-inflammatory drugs

KW - hyperalgesia

KW - allodynia

UR - https://www.scopus.com/pages/publications/85105117861

U2 - 10.1080/14756366.2021.1875459

DO - 10.1080/14756366.2021.1875459

M3 - Article

C2 - 33896320

SN - 1475-6366

VL - 36

SP - 940

EP - 953

JO - Journal of Enzyme Inhibition and Medicinal Chemistry

JF - Journal of Enzyme Inhibition and Medicinal Chemistry

IS - 1

ER -