Progress in the Discovery of BACE Inhibitors

Abstract

Dementia caused by Alzheimer's disease is a large medical burden on society in the developed world. Current treatments are largely symptomatic, and there is an urgent need for therapies which can interrupt or reverse the progression of disease. A number of strategies for intervention are being actively pursued; among the most promising is the inhibition of beta-secretase, or BACE. BACE is the enzyme responsible for N-terminal cleavage of the Alzheimer's precursor protein leading to the production of the beta-amyloid peptide. This cascade ultimately leads to the formation of amyloid plaques, one of the hallmark lesions of the disease. It is expected that inhibitors of BACE may therefore serve as an effective disease-modifing therapy for the treatment of AD. This concept has received significant attention by both academics and the pharmaceutical industry. This review focuses on a discussion of the reported structure-activity relationships for inhibitors of this important therapeutic target.

Alzheimer's Disease: From Pathology to Therapeutic Approaches

“…[285][286][287]). However, what is still lacking are published reports which demonstrate a robust activity in vivo after oral application in one of the models previously used for the development of g-secretase inhibitors (such as the APP-transgenic mouse or the wild-type rat).…”

Treatment Strategies Targeting Amyloid -Protein

“…Furthermore, selectivity for inhibition of BACE1 over related aspartyl proteases, such as BACE2 and cathepsin-D, was an additional constraint imposed on potential clinical candidates, in light of the antagonistic amyloidogenic activity of BACE2 (Farzan et al 2000;Yan et al 2001;Fluhrer et al 2002;Basi et al 2003) and the essential role of cathepsin-D in lysosomal function (Saftig et al 1996;Benes et al 2008). The interested reader is directed to expert medicinal chemistry reviews for structure -activity relationship studies toward the objectives of CNS-active, BACE1-selective, drug-like inhibitors (Hussain 2004;Thompson et al 2005;Durham and Shepherd 2006;John 2006;Ziora et al 2006;Ghosh et al 2008;Silvestri 2008;Hamada and Kiso 2009;Stachel 2009). Incompatibility between MW constraints (imposed by potency requirements) and size (for CNS permeability) have proven to be significant challenges in overcoming the p-gylcoproteinmediated efflux of BACE1 inhibitors from the CNS and has slowed advancement into the clinic of the many research efforts that were launched to discover and develop BACE inhibitors for treatment of AD.…”

Nanoparticles for the Treatment ofAlzheimer's Disease: Theoretical Rationale, Present Status and Future Perspectives

“…Studies, albeit controversial studies, show that the accumulation of Ab derived from APP by proteolytic cleavage are neurotoxic and believed to be responsible for the neurodegeneration observed in AD [194,195]. Therefore, preventing and reversing the Ab accumulation is an important pharmacological target in AD treatment and several potential therapeutics such as b-sheet breakers [196,197], regulators of APP translation [66,[198][199][200], inhibitors of APP secretases [69][70][71][72][73][74], vaccines against Ab [48] and metal chelators [42, [76][77][78]] have been developed and tested. As many potential drugs are electrically charged hydrophilic and/or large size molecules, a lack of ability to enter the brain may hamper their treatment efficacy.…”

“…Other medications and substances being investigated at the present time include cannabinoids, physostigmine, nerve growth factor, b-sheet breakers, valproate, huperzine and nicotine [58][59][60][61][62][63][64][65]. New studies on the regulation of Ab protein precursor translation by Phenserine [66,67], the regulation of Ab by neprilysin [68], inhibition of the activity of amyloid precursor protein (APP) secretases [69][70][71][72][73][74] and CD45 [75] show promising progress toward the identification of new therapeutic agents. Other studies, such as targeting glycosaminoglycans or metalloprotein attenuating compounds, new chelation agents, tau phosphorylation inhibitors, NF-kB blocker, gene delivery and human embryonic stem cells are under investigation [51, 59, [76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95].…”