Synthesis and Biological Activity of Flurbiprofen Analogues as Selective Inhibitors of β-Amyloid_1-42Secretion

Abstract

Flurbiprofen, a nonsteroidal antiinflammatory drug (NSAID), has been recently described to selectively inhibit beta-amyloid(1)(-)(42) (Abeta42) 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 Abeta42 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 Abeta42 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 Abeta42 concentrations. These new flurbiprofen analogues represent potential drug candidates to be developed for the treatment of AD.

Selective modulation of amyloid‐β peptide degradation by flurbiprofen, fenofibrate, and related compounds regulates Aβ levels

“…This led to the theory that the SALAs acted via the modulation of Ab production through a shift in the site of c-secretase cleavage from position 42 to 38. In turn, the Ab 1-42 /Ab 1-38 ratio has been used as an optimization criterion in drug discovery (Narlawar et al 2006;Peretto et al 2005;Imbimbo et al 2007aImbimbo et al ,b, 2009. Drugs were identified, such as fenofibrate and celecoxib, which showed an opposite effect on the Ab 1-42 /Ab 1-38 peptide fragment ratio (for ease of reference we term these agents SARAs).…”

“…The term selective amyloid lowering agents (SALA) was coined for this 'new' drug class, represented by R-flurbiprofen (tarenflurbil), a drug that provided positive phase 2 clinical trial data in AD patients before failing in a phase 3 trial (Wilcock et al 2008). Changes in the levels of Ab by NSAID SALAs in vitro and in vivo has been widely explained by modulation of Ab production (Weggen et al 2001;Eriksen et al 2003;Narlawar et al 2006;Imbimbo et al 2007b;Stock et al 2006;Peretto et al 2005). A number of mechanisms have been proposed, including the direct modulation of c-secretase activity (Weggen et al 2001;Eriksen et al 2003), downregulation of b secretase (Sastre et al 2003(Sastre et al , 2006, and Rho inhibition (Zhou et al 2003).…”

1-(3′,4′-Dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-cyclopropanecarboxylic Acid (CHF5074), a Novel γ-Secretase Modulator, Reduces Brain β-Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease without Causing Peripheral Toxicity

“…At 100 M, CHF5074 does not alter the expression profile of several Notch intracellular domain-responsive genes (Imbimbo et al, 2007). In rats, CHF5074 is orally well absorbed (50%), and it is slowly eliminated from plasma (t 1/2 ϭ 20.7 h) (Peretto et al, 2005). In young Tg2576 transgenic mice, short-term oral dosing with CHF5074 causes dose-dependent reduction of plasma A␤42.…”

“…We have synthesized new NSAID derivatives endowed with selective A␤42-lowering activity but devoid of COX inhibitory activity, thus suitable for chronic use in AD patients (Peretto et al, 2005). Within this new chemical series, CHF5074 (Fig.…”

Novel flurbiprofen derivatives with improved brain delivery: synthesis, in vitro and in vivo evaluations

“…gastrointestinal adverse effects (Green et al, 2009;Imbimbo, 2009b). Preclinical studies had shown that tarenflurbil did not penetrate blood-brain barrier (BBB) satisfactorily in rodents, with a 1.3% ratio of cerebrospinal fluid (CSF) to plasma and negligible tarenflurbil level measured in the brain ($2 mM) (Peretto et al, 2005;Kukar et al, 2007). In addition, both the high affinity to serum albumin and the active efflux transport restricted the passive diffusion of FLU to the brain (Parepally et al, 2006).…”